| 1. |
- Criveanu, Dan, et al.
(author)
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Identification of a new Kir6 potassium channel and comparison of properties of Kir6 subtypes by structural modelling and molecular dynamics
- 2023
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In: International Journal of Biological Macromolecules. - : Elsevier BV. - 0141-8130 .- 1879-0003. ; 247
-
Journal article (peer-reviewed)abstract
- ATP-sensitive potassium ion channels (KATP) are transmembrane proteins that modulate insulin release and muscle contraction. KATP channels are composed of two types of subunit, Kir6 and SUR, which exist in two and three isoforms respectively with different tissue distribution. In this work, we identify a previously undescribed ancestral vertebrate gene encoding a Kir6-related protein that we have named Kir6.3, which may not have a SUR binding partner, unlike the other two Kir6 proteins. Whereas Kir6.3 was lost in amniotes including mammals, it is still present in several early-diverging vertebrate lineages such as frogs, coelacanth, and rayfinned fishes. Molecular dynamics (MD) simulations using homology models of Kir6.1, Kir6.2, and Kir6.3 from the coelacanth Latimeria chalumnae showed that the three proteins exhibit subtle differences in their dynamics. Steered MD simulations of Kir6-SUR pairs suggest that Kir6.3 has a lower binding affinity for the SUR proteins than either Kir6.1 or Kir6.2. As we found no additional SUR gene in the genomes of the species that have Kir6.3, it most likely forms a lone tetramer. These findings invite studies of the tissue distribution of Kir6.3 in relation to the other Kir6 as well as SUR proteins to determine the functional roles of Kir6.3.
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| 2. |
- Abalo, Xesus, 1976-, et al.
(author)
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Circadian regulation of phosphodiesterase 6 genes in zebrafish differs between cones and rods : Implications for photopic and scotopic vision
- 2020
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In: Vision Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0042-6989 .- 1878-5646. ; 166, s. 43-51
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Journal article (peer-reviewed)abstract
- A correlation is known to exist between visual sensitivity and oscillations in red opsin and rhodopsin gene expression in zebrafish, both regulated by the clock gene. This indicates that an endogenous circadian clock regulates behavioural visual sensitivity, apart from the regulation exerted by the pineal organ. However, the specific mechanisms for cones (photopic vision) and rods (scotopic vision) are poorly understood. In this work, we performed gene expression, cosinor and immunohistochemical analyses to investigate other key genes involved in light perception, encoding the different subunits of phosphodiesterase pde6 and transducin G alpha(T), in constant lighting conditions and compared to normal light-dark conditions. We found that cones display prominent circadian oscillations in mRNA levels for the inhibitory subunit gene pde6ha that could contribute to the regulation of photopic sensitivity by preventing overstimulation in photopic conditions. In rods, the mRNA levels of the inhibitory subunit gene pde6ga oscillate under normal conditions and dampen down in constant light but continue oscillating in constant darkness. There is an increase in total relative expression for pde6gb in constant conditions. These observations, together with previous data, suggest a complex regulation of the scotopic sensitivity involving endogenous and non-endogenous components, possibly present also in other teleost species. The G alpha(T) genes do not display mRNA oscillations and therefore may not be essential for the circadian regulation of photosensitivity. In summary, our results support different regulation for the zebrafish photopic and scotopic sensitivities and suggest circadian regulation of pde6ha as a key factor regulating photopic sensitivity, while the regulatory mechanisms in rods appear to be more complex.
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| 3. |
- Alexander, Stephen P. H., et al.
(author)
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The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
- 2023
-
In: BRITISH JOURNAL OF PHARMACOLOGY. - : British pharmacological society. - 0007-1188 .- 1476-5381. ; 180
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Journal article (peer-reviewed)abstract
- The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at . G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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| 4. |
- Almgren, Karin, et al.
(author)
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Vetenskapsrådets friande av forskningsfusk obegripligt
- 2011
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In: Dagens nyheter. - Stockholm. - 1101-2447.
-
Journal article (pop. science, debate, etc.)abstract
- Hård kritik mot friande beslut. Förra hösten fann vi att en medicinforskare fabricerat och förfalskat forskningsresultat. Det är den mest omfattande utredningen om forskningsfusk under efterkrigstiden. För två veckor sedan drog Vetenskapsrådets nye chef tillbaka utredningen med en motivering som är helt tagen ur luften. Beslutet riskerar att ytterligare försämra förtroendet för forskningen i Sverige och för arbetet mot forskningsfusk, skriver den expertgrupp i Vetenskapsrådet som utredde misstankarna mot forskaren.
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| 5. |
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| 6. |
- Blomkvist, Josefin, et al.
(author)
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Perspective on Roseroot (Rhodiola rosea) Studies
- 2009
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In: Planta Medica. - : Verlag KG Stuttgart -New York. - 0032-0943 .- 1439-0221. ; 75:11, s. 1187-1190
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Journal article (peer-reviewed)abstract
- Rhodiola rosea (roseroot) extract is a commercially successful product, primarily used to reduce the effect of fatigue on physical and mental performance. In this perspective we present our investigation of the most recent studies performed on human subjects. With a focus on the statistical methods we found considerable shortcomings in all but one of the studies that claim significant improvement from roseroot extract. Overall, the study designs have not been well explained. Experimental results have been confused and appear to be in some cases incorrect. Some of the conclusions are based on selected results and contradicting data have not been adequately taken into account. We point to other studies of higher quality performed on roseroot, several that found no significant effect and one that did. We conclude that the currently available evidence for the claimed effects is insufficient and that the effect of Rhodiola rosea is in need of further investigation before therapeutic claims can be made.
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| 7. |
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| 8. |
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| 9. |
- Bromée, Torun, 1973-
(author)
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Evolution and Pharmacology of Receptors for Bradykinin and Neuropeptide Y in Vertebrates
- 2005
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Doctoral thesis (other academic/artistic)abstract
- The bradykinin and neuropeptide Y (NPY) receptors belong to the superfamily of G-protein coupled receptors (GPCRs). The GPCRs form the largest class of therapeutic targets and it is therefore of great interest to investigate the pharmacological properties, functions and evolution of these receptors.Bradykinin (BK) is a nonapeptide that contributes to inflammatory responses, mediates pain signals and influences blood pressure. The two bradykinin receptor subtypes B1 and B2 are well characterized in mammals, but have received little attention in non-mammals. This thesis describes the cloning and characterization of the first piscine bradykinin receptor, from the Danio rerio (zebrafish). Ligand-receptor interactions were measured as production of intracellular inositol phosphate. Zebrafish BK activated the receptor with highest potency (pEC50=6.97±0.1) while mammalian BK was almost inactive. A complete alanine and D-amino acid scan of the BK peptide revealed important roles for receptor interaction for residues Gly4, Ser6, Pro7, Leu8 and Arg9. The receptor gene was mapped to chromosome 17 in the zebrafish genome in a region that shows conserved synteny to the human B1-B2 gene region on chromosome 14. The release of the zebrafish and pufferfish genomes enabled us to identify both B1 and B2 genes in Danio rerio and pufferfishes (Takifugu rubripes and Tetraodon nigroviridis) as well as the B1 gene in chicken. All of these species display conserved synteny of the gene region. Interestingly, the evolutionary rate is clearly greater for B1 than for B2. Kininogen, the precursor for bradykinin, is also located in a chromosome region with extensive conserved synteny.Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) comprise a family of related peptides and are involved in a variety of neuronal and endocrine functions. Receptor subtypes Y6 and Y7 were cloned and pharmacologically characterized in chicken. The genes are located one megabase apart on chromosome 13 in a region with conserved synteny to human chromosome 5. Porcine PYY bound to chicken Y6 with a Kd of 0.80±0.36 nM and chicken Y7 with a Kd of 0.14±0.01 nM. The Y6 mRNA is expressed in hypothalamus, gastrointestinal tract and adipose tissue and may be involved in appetite regulation like other NPY receptors. Chicken Y7 mRNA was only detected in adrenal gland. These results may help explain why these receptors have lost function in humans.
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| 10. |
- Bromée, Torun, et al.
(author)
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Neuropeptide Y-family receptors Y6 and Y7 in chicken : Cloning, pharmacological characterization, tissue distribution and conserved synteny with human chromosome region
- 2006
-
In: The FEBS Journal. - : Federation of European Biochemical Societies. - 1742-464X .- 1742-4658. ; 273:9, s. 2048-2063
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Journal article (peer-reviewed)abstract
- The peptides of the neuropeptide Y (NPY) family exert their functions, including regulation of appetite and circadian rhythm, by binding to G-protein coupled receptors. Mammals have five subtypes, named Y1, Y2, Y4, Y5 and Y6, and recently Y7 has been discovered in fish and amphibians. In chicken we have previously characterized the first four subtypes and here we describe Y6 and Y7. The genes for Y6 and Y7 are located 1 megabase apart on chromosome 13, which displays conserved synteny with human chromosome 5 that harbours the Y6 gene. The porcine PYY radioligand bound the chicken Y6 receptor with a Kd of 0.80 ± 0.36 nm. No functional coupling was demonstrated. The Y6 mRNA is expressed in hypothalamus, gastrointestinal tract and adipose tissue. Porcine PYY bound chicken Y7 with a Kd of 0.14 ± 0.01 nm (mean ± SEM), whereas chicken PYY surprisingly had a much lower affinity, with a Ki of 41 nm, perhaps as a result of its additional amino acid at the N terminus. Truncated peptide fragments had greatly reduced affinity for Y7, in agreement with its closest relative, Y2, in chicken and fish, but in contrast to Y2 in mammals. This suggests that in mammals Y2 has only recently acquired the ability to bind truncated PYY. Chicken Y7 has a much more restricted tissue distribution than other subtypes and was only detected in adrenal gland. Y7 seems to have been lost in mammals. The physiological roles of Y6 and Y7 remain to be identified, but our phylogenetic and chromosomal analyses support the ancient origin of these Y receptor genes by chromosome duplications in an early (pregnathostome) vertebrate ancestor.
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| 11. |
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| 12. |
- Bromée, Torun, et al.
(author)
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Uneven Evolutionary Rates of Bradykinin B1 and B2 Receptors in Vertebrate Lineages
- 2006
-
In: Gene. - : Elsevier. - 0378-1119 .- 1879-0038. ; 373, s. 100-108
-
Journal article (peer-reviewed)abstract
- Bradykinin acts through two receptor subtypes in mammals and generates a variety of responses including pain, inflammation and hypotension. The evolutionary history of the bradykinin system has been unclear due to shortage of information outside mammals. We describe here two receptor subtypes and the bradykinin precursor in three species of bony fish (the zebrafish Danio rerio, the Japanese pufferfish Takifugu rubripes, and the green spotted pufferfish Tetraodon nigroviridis) and chicken and analyze the relationships to mammals by a combination of phylogeny, conserved synteny and exon–intron organization. All of these species have two receptor genes located close to each other in a tandem formation, with the B2 gene 5′ to the B1 gene, in chromosomal regions displaying conserved synteny between the species (albeit conservation of synteny in zebrafish is still unclear due to poor genome assembly). The evolutionary rate differs between the two genes as well as between lineages leading to differing pharmacological properties for both B1 and B2 across vertebrate classes. Also the bradykinin precursor gene was identified in all of these species in a chromosome region with conserved synteny. The tissue distribution of mRNA in T. rubripes is similar for B1 and B2, suggesting more similar regulation for the two genes than in mammals. In conclusion, the receptor tandem duplication predates the divergence of ray-finned fish and tetrapods and no additional duplicates of the receptors or bradykinin seem to have survived the ray-finned fish tetraploidization.
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| 13. |
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| 14. |
- Cardoso, Joao C. R., et al.
(author)
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Corticotropin-Releasing Hormone (CRH) Gene Family Duplications in Lampreys Correlate With Two Early Vertebrate Genome Doublings
- 2020
-
In: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 14
-
Journal article (peer-reviewed)abstract
- The ancestor of gnathostomes (jawed vertebrates) is generally considered to have undergone two rounds of whole genome duplication (WGD). The timing of these WGD events relative to the divergence of the closest relatives of the gnathostomes, the cyclostomes, has remained contentious. Lampreys and hagfishes are extant cyclostomes whose gene families can shed light on the relationship between the WGDs and the cyclostome-gnathostome divergence. Previously, we have characterized in detail the evolution of the gnathostome corticotropin-releasing hormone (CRH) family and found that its five members arose from two ancestral genes that existed before the WGDs. The two WGDs resulted, after secondary losses, in one triplet consisting of CRH1, CRH2, and UCN1, and one pair consisting of UCN2 and UCN3. All five genes exist in representatives for cartilaginous fishes, ray-finned fishes, and lobe-finned fishes. Differential losses have occurred in some lineages. We present here analyses of CRH-family members in lamprey and hagfish by comparing sequences and gene synteny with gnathostomes. We found five CRH-family genes in each of two lamprey species (Petromyzon marinusandLethenteron camtschaticum) and two genes in a hagfish (Eptatretus burgeri). Synteny analyses show that all five lamprey CRH-family genes have similar chromosomal neighbors as the gnathostome genes. The most parsimonious explanation is that the lamprey CRH-family genes are orthologs of the five gnathostome genes and thus arose in the same chromosome duplications. This suggests that lampreys and gnathostomes share the same two WGD events and that these took place before the lamprey-gnathostome divergence.
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| 15. |
- Cardoso, Joao C. R., et al.
(author)
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Corticotropin-releasing hormone family evolution : five ancestral genes remain in some lineages
- 2016
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In: Journal of Molecular Endocrinology. - 0952-5041 .- 1479-6813. ; 57:1, s. 73-86
-
Journal article (peer-reviewed)abstract
- The evolution of the peptide family consisting of corticotropin-releasing hormone ( CRH) and the three urocortins ( UCN1-3) has been puzzling due to uneven evolutionary rates. Distinct gene duplication scenarios have been proposed in relation to the two basal rounds of vertebrate genome doubling ( 2R) and the teleost fish-specific genome doubling ( 3R). By analyses of sequences and chromosomal regions, including many neighboring gene families, we show here that the vertebrate progenitor had two peptide genes that served as the founders of separate subfamilies. Then, 2R resulted in a total of five members: one subfamily consists of CRH1, CRH2, and UCN1. The other subfamily contains UCN2 and UCN3. All five peptide genes are present in the slowly evolving genomes of the coelacanth Latimeria chalumnae ( a lobe-finned fish), the spotted gar Lepisosteus oculatus ( a basal ray-finned fish), and the elephant shark Callorhinchus milii ( a cartilaginous fish). The CRH2 gene has been lost independently in placental mammals and in teleost fish, but is present in birds ( except chicken), anole lizard, and the nonplacental mammals platypus and opossum. Teleost 3R resulted in an additional surviving duplicate only for crh1 in some teleosts including zebrafish ( crh1a and crh1b). We have previously reported that the two vertebrate CRH/UCN receptors arose in 2R and that CRHR1 was duplicated in 3R. Thus, we can now conclude that this peptide-receptor system was quite complex in the ancestor of the jawed vertebrates with five CRH/UCN peptides and two receptors, and that crh and crhr1 were duplicated in the teleost fish tetraploidization.
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| 16. |
- Cardoso, João C R, et al.
(author)
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New insights into the evolution of vertebrate CRH (corticotropin-releasing hormone) and invertebrate DH44 (diuretic hormone 44) receptors in metazoans
- 2014
-
In: General and Comparative Endocrinology. - : Elsevier BV. - 0016-6480 .- 1095-6840. ; 209:SI, s. 162-170
-
Journal article (peer-reviewed)abstract
- The corticotropin releasing hormone receptors (CRHR) and the arthropod diuretic hormone 44 receptors (DH44R) are structurally and functionally related members of the G protein-coupled receptors (GPCR) of the secretin-like receptor superfamily. We show here that they derive from a bilaterian predecessor. In protostomes, the receptor became DH44R that has been identified and functionally characterised in several arthropods but the gene seems to be absent from nematode genomes. Duplicate DH44R genes (DH44 R1 and DH44R2) have been described in some arthropods resulting from lineage-specific duplications. Recently, CRHR-DH44R-like receptors have been identified in the genomes of some lophotrochozoans (molluscs, which have a lineage-specific gene duplication, and annelids) as well as representatives of early diverging deuterostomes. Vertebrates have previously been reported to have two CRHR receptors that were named CRHR1 and CRHR2. To resolve their origin we have analysed recently assembled genomes from representatives of early vertebrate divergencies including elephant shark, spotted gar and coelacanth. We show here by analysis of synteny conservation that the two CRHR genes arose from a common ancestral gene in the early vertebrate tetraploidizations (2R) approximately 500 million years ago. Subsequently, the teleost-specific tetraploidization (3R) resulted in a duplicate of CRHR1 that has been lost in some teleost lineages. These results help distinguish orthology and paralogy relationships and will allow studies of functional conservation and changes during evolution of the individual members of the receptor family and their multiple native peptide agonists.
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| 17. |
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| 18. |
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| 19. |
- Do Rego, Jean-Luc, et al.
(author)
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Steroid biosynthesis within the frog brain : a model of neuroendocrine regulation
- 2009
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In: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1163, s. 83-92
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Journal article (peer-reviewed)abstract
- There is now clear evidence that the brain, similar to the adrenal gland, gonads, and placenta, is a steroidogenic organ. Notably in the frog brain, the presence of various steroidogenic enzymes has been detected by immunohistochemistry in specific populations of neurons and/or glial cells. These steroidogenic enzymes are biologically active, as shown by the ability of brain tissue explants to convert [(3)H]pregnenolone into various radiolabeled steroids. The frog brain has also been extensively used as a model to study the mechanism of regulation of neurosteroidogenesis by neurotransmitters and neuropeptides. It has been demonstrated that the biosynthesis of neurosteroids is inhibited by gamma-aminobutyric acid (GABA), acting through GABA(A) receptors, and neuropeptide Y, acting through Y1 receptors, and is stimulated by the octadecaneuropeptide (ODN), acting through central-type benzodiazepine receptors, triakontatetraneuropeptide (TTN), acting through peripheral-type benzodiazepine receptors, and vasotocin, acting through V1a-like receptors. These data indicate that some of the neurophysiological effects of neurotransmitters and neuropeptides may be mediated through modulation of neurosteroid biosynthesis.
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| 20. |
- Dreborg, Susanne, et al.
(author)
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Evolution of vertebrate opioid receptors
- 2008
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 105:40, s. 15487-15492
-
Journal article (peer-reviewed)abstract
- The opioid peptides and receptors have prominent roles in pain transmission and reward mechanisms in mammals. The evolution of the opioid receptors has so far been little studied, with only a few reports on species other than tetrapods. We have investigated species representing a broader range of vertebrates and found that the four opioid receptor types (delta, kappa, mu, and NOP) are present in most of the species. The gene relationships were deduced by using both phylogenetic analyses and chromosomal location relative to 20 neighboring gene families in databases of assembled genomes. The combined results show that the vertebrate opioid receptor gene family arose by quadruplication of a large chromosomal block containing at least 14 other gene families. The quadruplication seems to coincide with, and, therefore, probably resulted from, the two proposed genome duplications in early vertebrate evolution. We conclude that the quartet of opioid receptors was already present at the origin of jawed vertebrates approximately 450 million years ago. A few additional opioid receptor gene duplications have occurred in bony fishes. Interestingly, the ancestral receptor gene duplications coincide with the origin of the four opioid peptide precursor genes. Thus, the complete vertebrate opioid system was already established in the first jawed vertebrates.
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| 21. |
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| 22. |
- Dyakova, Olga
(author)
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The processing of natural images in the visual system
- 2017
-
Doctoral thesis (other academic/artistic)abstract
- Any image can be described in terms of its statistics (i.e. quantitative parameters calculated from the image, for example RMS-contrast, the skewness of image brightness distribution, and slope constant of an average amplitude spectrum).It was previously shown that insect and vertebrate visual systems are optimised to the statistics common among natural scenes. However, the exact mechanisms of this process are still unclear and need further investigation.This thesis presents the results of examining links between some image statistics and visual responses in humans and hoverflies.It was found that while image statistics do not play the main role when hoverflies (Eristalis tenax and Episyrphus balteatus) chose what flowers to feed on, there is a link between hoverfly (Episyrphus balteatus) active behaviours and image statistics. There is a significant difference in the slope constant of the average amplitude spectrum, RMS contrast and skewness of brightness distribution between photos of areas where hoverflies were hovering or flying. These photos were also used to create a prediction model of hoverfly behaviour. After model validation, it was concluded that photos of both the ground and the surround should be used for best prediction of behaviour. The best predictor was skewness of image brightness distribution.By using a trackball setup, the optomotor response in walking hoverflies (Eristalis tenax) was found to be influenced by the slope constant of an average amplitude spectrum. Intracellular recording showed that the higher-order neuron cSIFE (The centrifugal stationary inhibited flicker excited) in the hoverfly (Eristalis tenax) lobula plate was inhibited by a range of natural scenes and that this inhibition was strongest in a response to visual stimuli with the slope constant of an average amplitude spectrum of 1, which is the typical value for natural environments. Based on the results of psychophysics study in human subjects it was found that sleep deprivation affects human perception of naturalistic slope constants differently for different image categories (“food” and “real world scenes”).These results help provide a better understanding of the link between visual processes and the spatial statistics of natural scenes.
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| 23. |
- Elphick, Maurice R., et al.
(author)
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Evolution of neuropeptide signalling systems
- 2018
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In: Journal of Experimental Biology. - : COMPANY OF BIOLOGISTS LTD. - 0022-0949 .- 1477-9145. ; 221:3
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Research review (peer-reviewed)abstract
- Neuropeptides are a diverse class of neuronal signalling molecules that regulate physiological processes and behaviour in animals. However, determining the relationships and evolutionary origins of the heterogeneous assemblage of neuropeptides identified in a range of phyla has presented a huge challenge for comparative physiologists. Here, we review revolutionary insights into the evolution of neuropeptide signalling that have been obtained recently through comparative analysis of genome/transcriptome sequence data and by 'deorphanisation' of neuropeptide receptors. The evolutionary origins of at least 30 neuropeptide signalling systems have been traced to the common ancestor of protostomes and deuterostomes. Furthermore, two rounds of genome duplication gave rise to an expanded repertoire of neuropeptide signalling systems in the vertebrate lineage, enabling neofunctionalisation and/or subfunctionalisation, but with lineage-specific gene loss and/or additional gene or genome duplications generating complex patterns in the phylogenetic distribution of paralogous neuropeptide signalling systems. We are entering a new era in neuropeptide research where it has become feasible to compare the physiological roles of orthologous and paralogous neuropeptides in a wide range of phyla. Moreover, the ambitious mission to reconstruct the evolution of neuropeptide function in the animal kingdom now represents a tangible challenge for the future.
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| 24. |
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| 25. |
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| 26. |
- Fällmar, Helena, 1980-, et al.
(author)
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Identification of positions in the human neuropeptide Y/peptide YY receptor Y2 that contribute to pharmacological differences between receptor subtypes
- 2011
-
In: Neuropeptides. - : Elsevier BV. - 0143-4179 .- 1532-2785. ; 45:4, s. 293-300
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Journal article (peer-reviewed)abstract
- The members of the neuropeptide Y (NPY) family are key players in food-intake regulation. In humans this family consists of NPY, peptide YY (PYY) and pancreatic polypeptide (PP) which interact with distinct preference for the four receptors showing very low sequence identity, i.e. Y1, Y2, Y4 and Y5. The binding of similar peptides to these divergent receptors makes them highly interesting for mutagenesis studies. We present here a site-directed mutagenesis study of four amino acid positions in the human Y2 receptor. T(3.40) was selected based on sequence alignments both between subtypes and between species and G(2.68), L(4.60) and Q(6.55) also on previous binding studies of the corresponding positions in the Y1 receptor. The mutated receptors were characterized pharmacologically with the peptide agonists NPY, PYY, PYY(3-36), NPY(13-36) and the non-peptide antagonist BIIE0246. Interestingly, the affinity of NPY and PYY(3-36) increased for the mutants T(3.40)I and Q(6.55)A. Increased affinity was also observed for PYY to Q(6.55)A. PYY(3-36) displayed decreased affinity for G(2.68)N and L(4.60)A whereas binding of NPY(13-36) was unaffected by all mutations. The antagonist BIIE0246 showed decreased affinity for T(3.40)I, L(4.60)A and Q(6.55)A. Although all positions investigated were found important for interaction with at least one of the tested ligands the corresponding positions in hY1 seem to be of greater importance for ligand binding. Furthermore these data indicate that binding of the agonists and the antagonist differs in their points of interaction. The increase in the binding affinity observed may reflect an indirect effect caused by a conformational change of the receptor. These findings will help to improve the structural models of the human NPY receptors.
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| 27. |
- Fällmar, Helena, 1980-, et al.
(author)
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Neuropeptide Y/peptide YY receptor Y2 duplicate in zebrafish with unique introns displays distinct peptide binding properties
- 2011
-
In: Comparative Biochemistry and Physiology - Part B. - : Elsevier BV. - 1096-4959 .- 1879-1107. ; 160:4, s. 166-173
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Journal article (other academic/artistic)abstract
- The neuropeptide Y-family peptides and receptors are involved in a broad range of functions including appetite regulation. Both the peptide genes and the receptor genes are known to have duplicated in early vertebrate evolution. The ancestral jawed vertebrate had 7 NPY receptors but the number varies between 4 and 7 in extant vertebrates. Herein we describe the identification of an additional NPY receptor in two fish species, zebrafish and medaka. They cluster together with the Y2 receptors in phylogenetic analyses and seem to be orthologous to each other that is why we have named them Y2-2. Their genes differ from Y2 in having introns in the coding region. Binding studies with zebrafish Y2-2 receptors show that the three endogenous peptides NPY, PYYa and PYYb have similar affinities, 0.15-0.66nM. This is in contrast to the Y2 receptor where they differed considerably from one another. N-terminally truncated NPY binds poorly and the Y2 antagonist BIIE0246 binds well to Y2-2, results that are reversed in comparison to Y2. Zebrafish Y2-2 mRNA was detected by PCR in the intestine and the eye, but not in the brain. In conclusion, we have found a novel Y2-like NPY/PYY receptor that probably arose in early teleost fish evolution.
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| 28. |
- Fällmar, Helena, 1980-
(author)
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Studies of the Neuropeptide Y Receptor Y2 in Human and Zebrafish
- 2011
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Doctoral thesis (other academic/artistic)abstract
- The G-protein coupled receptors (GPCRs) comprise the largest family of receptors in humans and other vertebrates. They are embedded in the cell membrane and are activated by many different signaling molecules. Activation modulates cellular signal transduction pathways and influences many physiological processes. Therefore the GPCRs are important as targets for numerous drugs. The receptors for NPY (neuropeptide Y) belong to GPCRs of Class A (rhodopsin-like). NPY and its related peptides PYY and PP are involved in the regulation of appetite, blood pressure and many other processes. They share a common structure and interact with the receptors Y1, Y2, Y4 and Y5 in mammals, and, in addition, Y7 and Y8 in amphibians and bony fishes. This thesis is focused on the human Y2 receptor, known to reduce appetite, by investigating the importance of thirteen amino acid residues for ligand binding. Mutagenesis followed by functional expression and receptor binding was conducted. During the course of this work several new GPCR crystal structures have been resolved, thereby improving the receptor modeling in papers I-III. The major finding is that even though the Y1 and Y2 receptors have evolved from a common ancestor, their points of ligand interaction differ and have thus changed during evolution. In general, the positions investigated resulted in milder changes in the ligands’ affinities for Y2 compared to Y1. These findings were incorporated in the design of new Y1 and Y2 receptor models, leading to improved understanding of how such divergent receptors, sharing only 30 percent sequence identity, can still interact with the same ligands. Notably, several of the mutations introduced in Y2 resulted in increased affinity. A novel NPY receptor gene named Y2-2 was identified in the genomes of zebrafish and medaka. This brings the number of zebrafish NPY receptors to seven. The binding characteristics of zebrafish Y2-2 differed from zebrafish Y2 mainly in the interaction with NPY13-36 and the antagonist BIIE0246. In conclusion, these results increase our understanding of ligand interactions with GPCRs and will be useful for refinement of ligand-receptor models for future development of receptor subtype-selective drugs.
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| 29. |
- Gao, Tianle, et al.
(author)
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The Neuropeptide Y System Regulates Both Mechanical and Histaminergic Itch
- 2018
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In: Journal of Investigative Dermatology. - : ELSEVIER SCIENCE INC. - 0022-202X .- 1523-1747. ; 138:11, s. 2405-2411
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Journal article (peer-reviewed)abstract
- Itch is a somatosensory modality that serves to alert an organism to harmful elements removable by scratching, such as parasites and chemical irritants. Recently, ablation or silencing of neuropeptide Y (NPY)-expressing spinal interneurons was reported to selectively enhance mechanical itch, whereas chemical itch was unaffected. We examined the effect of activating the NPY/Y-1 receptor system on scratch behavior in mice. We found that intrathecal administration of the Y-1 agonist [Leu(31), Pro(34)]-NPY (LP-NPY) attenuated itch behavior induced by application of 0.07 g von Frey filament in the nape of the neck compared with saline treatment, indicating that activation of the spinal NPY/Y-1 system dampens mechanical itch. However, intrathecal administration of LP-NPY also attenuated chemically induced scratching provoked by intradermal application of histamine or the mast cell degranulator 48/80 (histaminergic itch), and the latter effect could be reversed by administration of the Y-1 antagonist BIBO3304. Intrathecal application of the native nonselective agonist NPY also attenuated histamine or 48/80-induced scratching. Our analyses emphasize the importance of including additional quantitative parameters to characterize the full spectrum of itch behavior and show that the NPY/Y-1 system dampens both mechanically and chemically induced scratching and hence is shared by the two submodalities of itch.
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| 30. |
- Garcia-Concejo, Adrian, et al.
(author)
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Protein kinase C family evolution in jawed vertebrates
- 2021
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In: Developmental Biology. - : Elsevier. - 0012-1606 .- 1095-564X. ; 479, s. 77-90
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Journal article (peer-reviewed)abstract
- Protein kinase C (PKC) was one of the first kinases identified in human cells. It is now known to constitute a family of kinases that respond to diacylglycerol, phosphatidylserine and for some family members, Ca2+. They have a plethora of different functions, such as cell cycle regulation, immune response and memory formation. In mammals, 12 PKC family members have been described, usually divided into 4 different subfamilies. We present here a comprehensive evolutionary analysis of the PKC genes in jawed vertebrates with special focus on the impact of the two tetraploidizations (1R and 2R) before the radiation of jawed vertebrates and the teleost tetraploidization (3R), as illuminated by synteny and paralogon analysis including many neighboring gene families. We conclude that the vertebrate predecessor had five PKC genes, as tunicates and lancelets still do, and that the PKC family should therefore ideally be organized into five subfamilies. The 1R and 2R events led to a total of 12 genes distributed among these five subfamilies. All 12 genes are still present in some of the major lineages of jawed vertebrates, including mammals, whereas birds and cartilaginous fishes have lost one member. The 3R event added another nine genes in teleosts, bringing the total to 21 genes. The zebrafish, a common experimental model animal, has retained 19. We have found no independent gene duplications. Thus, the genome doublings completely account for the complexity of this gene family in jawed vertebrates and have thereby had a huge impact on their evolution.
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| 31. |
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| 32. |
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| 33. |
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| 34. |
- Granas, Charlotta, et al.
(author)
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Mutagenesis of the human 5-HT1B receptor : Differences from the closely related 5-HT1A receptor and the role of residue F331 in signal transduction
- 1998
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In: Journal of Receptor and Signal Transduction Research. - : MARCEL DEKKER INC. - 1079-9893 .- 1532-4281. ; 18:4-6, s. 225-241
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Journal article (peer-reviewed)abstract
- We have used a combination of sequence comparisons, computer-based modeling and site-directed mutagenesis to investigate the molecular interactions involved in ligand binding and signal transduction of the human 5-HT1B receptor. Two amino acid residues, S212 in transmembrane region (TM) V and F331 in TM VI, were replaced by alanines. These amino acids are conserved in many G protein-coupled receptors and therefore likely to be important for receptor function. The mutant receptors were expressed in Chinese hamster ovary cells. The 5-HT-like agonist 5-carboxamidotryptamine (5-CT) bound with 15-fold lower affinity to the S212A mutant as compared to wild-type receptor and the antagonist methiothepin bound with 17-fold lower affinity to the F331A mutant. No reduction in the affinity of 5-HT was seen for the S212A mutant, although an equivalent mutation in the 5-HT1A receptor resulted in a 100-fold reduction of 5-HT binding. The inhibition of forskolin-stimulated cyclic AMP production by 5-HT was significantly reduced in cells expressing the F331A mutant, even though the endogenous ligand 5-HT bound with somewhat increased affinity. Methiothepin acted as an inverse agonist and increased the forskolin-stimulated cyclic AMP production at both the wild-type receptor and the mutants, and the effect was stronger on the F331A mutant. These results suggest that F331 is involved in the conformational changes necessary for signal transduction.
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| 35. |
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| 36. |
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| 37. |
- Gruber, Kenneth A, et al.
(author)
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Neuropeptide Y and gamma-melanocyte stimulating hormone (gamma-MSH) share a common pressor mechanism of action
- 2009
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In: Endocrine. - : Springer Science and Business Media LLC. - 1355-008X .- 1559-0100. ; 35:3, s. 312-324
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Journal article (peer-reviewed)abstract
- Central circuits known to regulate food intake and energy expenditure also affect central cardiovascular regulation. For example, both the melanocortin and neuropeptide Y (NPY) peptide families, known to regulate food intake, also produce central hypertensive effects. Members of both families share a similar C-terminal amino acid residue sequence, RF(Y) amide, a sequence distinct from that required for melanocortin receptor binding. A recently delineated family of RFamide receptors recognizes both of these C-terminal motifs. We now present evidence that an antagonist with Y1 and RFamide receptor activity, BIBO3304, will attenuate the central cardiovascular effects of both gamma-melanocyte stimulating hormone (gamma-MSH) and NPY. The use of synthetic melanocortin and NPY peptide analogs excluded an interaction with melanocortin or Y family receptors. We suggest that the anatomical convergence of NPY and melanocortin neurons on cardiovascular control centers may have pathophysiological implications through a common or similar RFamide receptor(s), much as they converge on other nuclei to coordinately control energy homeostasis.
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| 38. |
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| 39. |
- Göktürk, Camilla, 1967-
(author)
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Semicarbazide-sensitive Amine Oxidase (SSAO) – Regulation and Involvement in Blood Vessel Damage with Special Regard to Diabetes : A Study on Mice Overexpressing Human SSAO
- 2004
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Doctoral thesis (other academic/artistic)abstract
- Semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6) belongs to a family of copper-containing amine oxidases. SSAO exists as a membrane bound protein in endothelial-, smooth muscle-, and adipose cells as well as soluble in plasma. SSAO catalyses oxidative deamination of primary monoamines, which results in the production of corresponding aldehydes, hydrogen peroxide and ammonia. These compounds are very reactive and potentially cytotoxic, and are able to induce vascular damage if produced in high levels. Patients with diabetes mellitus, and with diabetic complications in particular, have a higher SSAO activity in plasma compared to healthy controls. It has therefore been speculated that high SSAO activity is involved in the development of vascular complications associated with diabetes. The aim of this thesis is to investigate the importance of SSAO in the development of disorders of a vascular origin. We have studied the transcriptional regulation of the SSAO gene, by inducing diabetes in NMRI and in transgenic mice, overexpressing the human form of SSAO in smooth muscle cells. We found that the increase in SSAO activity in diabetes is accompanied by reduced mRNA levels of the endogenous mouse gene, suggesting a negative feedback on the transcription of the SSAO gene. In addition, the transgenic mice exhibited an abnormal phenotype in the elastic tissue of aorta and renal artery. These mice have a lower mean artery pressure and an elevated pulse pressure. These results indicate that high SSAO activity in smooth muscle cells is associated with a change in the morphology of large arteries. This is likely contributing to the development of vascular complications in diabetes.
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| 40. |
- Haitina, Tatjana, et al.
(author)
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Cloning, tissue distribution, pharmacology and three-dimensional modelling of melanocortin receptors 4 and 5 in rainbow trout suggest close evolutionary relationship of these subtypes
- 2004
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In: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 380:2, s. 475-486
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Journal article (peer-reviewed)abstract
- The rainbow trout (Oncorhynchus mykiss) is one of the most widely used fish species in aquaculture and physiological research. In the present paper, we report the first cloning, 3D (three-dimensional) modelling, pharmacological characterization and tissue distribution of two melanocortin (MC) receptors in rainbow trout. Phylogenetic analysis indicates that these receptors are orthologues of the human MC4 and MC5 receptors. We created 3D molecular models of these rainbow trout receptors and their human counterparts. These models suggest greater divergence between the two human receptors than between their rainbow trout counterparts. The pharmacological analyses demonstrated that ACTH (adrenocorticotropic hormone) had surprisingly high affinity for the rainbow trout MC4 and MC5 receptors, whereas alpha-, beta- and gamma-MSH (melanocyte-stimulating hormone) had lower affinity. In second-messenger studies, the cyclic MSH analogues MTII and SHU9119 acted as potent agonist and antagonist respectively at the rainbow trout MC4 receptor, indicating that these ligands are suitable for physiological studies in rainbow trout. Interestingly, we found that the rainbow trout MC4 receptor has a natural high-affinity binding site for zinc ions (0.5 microM) indicating that zinc may play an evolutionary conserved role at this receptor. Reverse transcription PCR indicates that the rainbow trout receptors are expressed both in peripheral tissues and in the central nervous system, including the telencephalon, optic tectum and hypothalamus. Overall, this analysis indicates that the rainbow trout MC4 and MC5 receptors have more in common than their mammalian counterparts, which may suggest that these two receptors have a closer evolutionary relationship than the other MC receptor subtypes.
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| 41. |
- Hallbeck, Martin, 1970-, et al.
(author)
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Neuropeptide expression in rat paraventricular hypothalamic neurons that project to the spinal cord
- 2001
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In: Journal of Comparative Neurology. - : Wiley. - 0021-9967 .- 1096-9861. ; 433:2, s. 222-238
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Journal article (peer-reviewed)abstract
- The paraventricular hypothalamic nucleus (PVH) exerts many of its regulatory functions through projections to spinal cord neurons that control autonomic and sensory functions. By using in situ hybridization histochemistry in combination with retrograde tract tracing, we analyzed the peptide expression among neurons in the rat PVH that send axons to the spinal cord. Projection neurons were labeled by immunohistochemical detection of retrogradely transported cholera toxin subunit B, and radiolabeled long riboprobes were used to identify neurons containing dynorphin, enkephalin, or oxytocin mRNA. Of the spinally projecting neurons in the PVH, approximately 40% expressed dynorphin mRNA, 40% expressed oxytocin mRNA, and 20% expressed enkephalin mRNA. Taken together with our previous findings on the distribution of vasopressin-expressing neurons in the PVH (Hallbeck and Blomqvist [1999] J. Comp. Neurol. 411:201–211), the results demonstrated that the different PVH subdivisions display distinct peptide expression patterns among the spinal cord–projecting neurons. Thus, the lateral parvocellular subdivision contained large numbers of spinal cord–projecting neurons that express any of the four investigated peptides, whereas the ventral part of the medial parvocellular subdivision displayed a strong preponderance for dynorphin- and vasopressin-expressing cells. The dorsal parvocellular subdivision almost exclusively contained dynorphin- and oxytocin-expressing spinal cord–projecting neurons. This parcellation of the peptide-expressing neurons suggested a functional diversity among the spinal cord–projecting subdivisions of the PVH that provide an anatomic basis for its various and distinct influences on autonomic and sensory processing at the spinal level.
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| 42. |
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| 43. |
- Holmberg, Sara K S, et al.
(author)
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Localization of neuropeptide Y receptor Y5 mRNA in the guinea pig brain
- 2004
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In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 117, s. 61-67
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Journal article (peer-reviewed)abstract
- Neuropeptide Y (NPY) has prominent stimulatory effects on food intake in virtually all animals that have been studied. In mammals, the effect is primarily mediated by receptors Y1 and Y5, which seem to contribute to different aspects of feeding behavior in guinea pigs and rats/mice. Interestingly, differences in receptor distribution among mammalian species have been reported. To get a broader perspective on the role of Y5, we describe here studies of guinea pig (Cavia porcellus), a species which due to its phylogenetic position in the mammalian radiation is an interesting complement to previous studies in rat and mouse. Guinea pig brain sections were hybridized with two 35S-labeled oligonucleotides complementary to Y5 mRNA. The highest expression levels of Y5 mRNA were observed in the hippocampus and several hypothalamic and brain stem nuclei implicated in the regulation of feeding, such as the paraventricular, arcuate and ventromedial hypothalamic nuclei. This contrasts with autoradiography studies that detected low Y5-like binding in these areas, a discrepancy observed also in rat and human. Y5 mRNA expression was also seen in the striatum, in great contrast to mouse and rat. Taken together, these data show that Y5 mRNA distribution displays some interesting species differences, but that its expression in feeding centers seems to be essentially conserved among mammals, adding further support for an important role in food intake.
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| 44. |
- Hultqvist, Greta, et al.
(author)
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Evolution of the Vertebrate Paralemmin Gene Family : Ancient Origin of Gene Duplicates Suggests Distinct Functions
- 2012
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:7, s. e41850-
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Journal article (peer-reviewed)abstract
- Paralemmin-1 is a protein implicated in plasma membrane dynamics, the development of filopodia, neurites and dendritic spines, as well as the invasiveness and metastatic potential of cancer cells. However, little is known about its mode of action, or about the biological functions of the other paralemmin isoforms: paralemmin-2, paralemmin-3 and palmdelphin. We describe here evolutionary analyses of the paralemmin gene family in a broad range of vertebrate species. Our results suggest that the four paralemmin isoform genes (PALM1, PALM2, PALM3 and PALMD) arose by quadruplication of an ancestral gene in the two early vertebrate genome duplications. Paralemmin-1 and palmdelphin were further duplicated in the teleost fish specific genome duplication. We identified a unique sequence motif common to all paralemmins, consisting of 11 highly conserved residues of which four are invariant. A single full-length paralemmin homolog with this motif was identified in the genome of the sea lamprey Petromyzon marinus and an isolated putative paralemmin motif could be detected in the genome of the lancelet Branchiostoma floridae. This allows us to conclude that the paralemmin gene family arose early and has been maintained throughout vertebrate evolution, suggesting functional diversification and specific biological roles of the paralemmin isoforms. The paralemmin genes have also maintained specific features of gene organisation and sequence. This includes the occurrence of closely linked downstream genes, initially identified as a readthrough fusion protein with mammalian paralemmin-2 (Palm2-AKAP2). We have found evidence for such an arrangement for paralemmin-1 and -2 in several vertebrate genomes, as well as for palmdelphin and paralemmin-3 in teleost fish genomes, and suggest the name paralemmin downstream genes (PDG) for this new gene family. Thus, our findings point to ancient roles for paralemmins and distinct biological functions of the gene duplicates.
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| 45. |
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| 46. |
- Jakobsson, Joel, et al.
(author)
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Regulation of Synaptic Vesicle Budding and Dynamin Function by an EHD ATPase
- 2011
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In: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 31:39, s. 13972-13980
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Journal article (peer-reviewed)abstract
- Eps15 homology domain-containing proteins (EHDs) are conserved ATPases implicated in membrane remodeling. Recently, EHD1 was found to be enriched at synaptic release sites, suggesting a possible involvement in the trafficking of synaptic vesicles. We have investigated the role of an EHD1/3 ortholog (1-EHD) in the lamprey giant reticulospinal synapse. 1-EHD was detected by immunogold at endocytic structures adjacent to release sites. In antibody microinjection experiments, perturbation of 1-EHD inhibited synaptic vesicle endocytosis and caused accumulation of clathrin-coated pits with atypical, elongated necks. The necks were covered with helix-like material containing dynamin. To test whether 1-EHD directly interferes with dynamin function, we used fluid-supported bilayers as in vitro assay. We found that 1-EHD strongly inhibited vesicle budding induced by dynamin in the constant presence of GTP. 1-EHD also inhibited dynamin-induced membrane tubulation in the presence of GTP gamma S, a phenomenon linked with dynamin helix assembly. Our in vivo results demonstrate the involvement of 1-EHD in clathrin/dynamin-dependent synaptic vesicle budding. Based on our in vitro observations, we suggest that 1-EHD acts to limit the formation of long, unproductive dynamin helices, thereby promoting vesicle budding.
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| 47. |
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| 48. |
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| 49. |
- Kanders, Sofia H.
(author)
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The relationship between overweight and depression in view of genes, environment and their joint influence
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Obesity and depression are known to often go hand in hand, but is this due to our genetic heritage, environmental factors or a combination thereof? With a neuroscientific approach, I have investigated the relationship between obesity and depression with the aim of bridging the different levels of research available in order to better understand this complex topic. Using data from a longitudinal cohort with adults, we analysed the genetic contribution to antidepressant response in Study I. The association between antidepressant treatment and changes in body mass index, waist circumference and fat mass was assessed in Study II. In Study III, the importance of bullying victimization for the relationship between obesity and depression was analysed using a longitudinal cohort with adolescents. Lastly, the moderating effect from breastfeeding duration on the relation between a known obesity associated gene and body mass index among adolescents and young adults was examined in Study IV.The bidirectional relationship between obesity and depression is derived from several joint processes and mechanisms such as the stress system and symptomatology overlap with strong environmental influences affecting both disorders, plausibly through epigenetic processes. Even though overweight and obesity were associated with depressive symptoms, one even more important environmental factor for the development of symptoms was bullying victimization – a risk factor that persisted after six years of follow-up. The genetic contribution to these complex disorders from individual variations is small in most cases, but with a credible additive effect and with environmental factors as important moderators of these relationships. One such moderator is breastfeeding duration, which was found to contribute to the relationship between FTO and future BMI with different patterns for the individual variants, which supports the differential susceptibility hypothesis. Finally, when AD treatment is used, the patient should be monitored regularly, both regarding depressive symptoms as well as obesity-related measurements.Overall, it is of high importance to focus on prevention because the frequently chronic course of obesity, as well as depression, has a high burden on individuals, as well as on society.
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| 50. |
- Klockars, Anica, 1985-
(author)
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Non-caloric regulation of food intake
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Food intake is shaped by environmental, endocrine, metabolic, and reward-related signals. A change in appetite is an outcome of integration of the relevant external and internal stimuli. While the main purpose of eating is to reverse a negative energy balance, mechanisms protecting homeostasis change appetite for other reasons. This thesis examines the role of select brain mechanisms in regulating consumption driven by aspects other than energy.In paper I, an increased percentage of c-Fos positive OT neurons was observed after mice ingested sucrose, while no change was found after Intralipid intake. Given a choice between isocaloric sugar and Intralipid solutions, mice injected with an OT receptor antagonist increase their preference for sucrose, while total calorie intake remains unchanged, suggesting that OT prevents overconsumption of sugar.Paper II addresses whether MCH, which has anxiolytic properties and mediates reward-motivated feeding, has the ability to alleviate conditioned taste aversion in rats. We found that while mRNA expression of MCH and its receptor are changed in aversive animals, central injections of MCH do not prevent the acquisition of aversion, nor do they affect the rate of extinction of the taste aversion.Paper III describes evidence that the N/OFQ system facilitates food intake by alleviating aversive responsiveness. Blocking the NOP receptor delays extinction of aversion and reduces food intake in hungry rats.Paper IV reports that leucine ingestion increases mRNA expression levels of genes known to mediate reward, as well as orexigenic gene expression in the nucleus accumbens (Nacc), a key component of the reward circuit. Adding leucine to drinking water increases activity of the reward system, which possibly contributes to the pleasure of consumption.A separate approach using Drosophila melanogaster is introduced in paper V which provides evidence that knocking down the gene for the transcription factor Ets96B during development results in a simultaneous disruption in sleep patterns and appetite, thus highlighting the interplay between these physiological parameters.We conclude that OT, MCH, N/OFQ and Ets96B belong to mechanisms regulating food intake for reasons other than energy balance. Composition of food and negative associations with diets affect neural networks controlling appetite.
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