| 1. |
- Criveanu, Dan, et al.
(författare)
-
Identification of a new Kir6 potassium channel and comparison of properties of Kir6 subtypes by structural modelling and molecular dynamics
- 2023
-
Ingår i: International Journal of Biological Macromolecules. - : Elsevier BV. - 0141-8130 .- 1879-0003. ; 247
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 2. |
- Abalo, Xesus, 1976-, et al.
(författare)
-
Circadian regulation of phosphodiesterase 6 genes in zebrafish differs between cones and rods : Implications for photopic and scotopic vision
- 2020
-
Ingår i: Vision Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0042-6989 .- 1878-5646. ; 166, s. 43-51
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 3. |
- Alexander, Stephen P. H., et al.
(författare)
-
The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
- 2023
-
Ingår i: BRITISH JOURNAL OF PHARMACOLOGY. - : British pharmacological society. - 0007-1188 .- 1476-5381. ; 180
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 4. |
- Cardoso, Joao C. R., et al.
(författare)
-
Corticotropin-Releasing Hormone (CRH) Gene Family Duplications in Lampreys Correlate With Two Early Vertebrate Genome Doublings
- 2020
-
Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 14
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 5. |
- Elphick, Maurice R., et al.
(författare)
-
Evolution of neuropeptide signalling systems
- 2018
-
Ingår i: Journal of Experimental Biology. - : COMPANY OF BIOLOGISTS LTD. - 0022-0949 .- 1477-9145. ; 221:3
-
Forskningsöversikt (refereegranskat)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.
|
|
| 6. |
- Fears, R., et al.
(författare)
-
Assessing and regulating homeopathic products
- 2017
-
Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 282:6, s. 563-565
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 7. |
|
|
| 8. |
- Gao, Tianle, et al.
(författare)
-
The Neuropeptide Y System Regulates Both Mechanical and Histaminergic Itch
- 2018
-
Ingår i: Journal of Investigative Dermatology. - : ELSEVIER SCIENCE INC. - 0022-202X .- 1523-1747. ; 138:11, s. 2405-2411
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 9. |
- Garcia-Concejo, Adrian, et al.
(författare)
-
Protein kinase C family evolution in jawed vertebrates
- 2021
-
Ingår i: Developmental Biology. - : Elsevier. - 0012-1606 .- 1095-564X. ; 479, s. 77-90
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 10. |
- Gruber, Kenneth A, et al.
(författare)
-
Neuropeptide Y and gamma-melanocyte stimulating hormone (gamma-MSH) share a common pressor mechanism of action
- 2009
-
Ingår i: Endocrine. - : Springer Science and Business Media LLC. - 1355-008X .- 1559-0100. ; 35:3, s. 312-324
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 11. |
- Kanders, Sofia H.
(författare)
-
The relationship between overweight and depression in view of genes, environment and their joint influence
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
|
|
| 12. |
- Lagman, David, 1987-, et al.
(författare)
-
Ancient multiplicity in cyclic nucleotide-gated (CNG) cation channel repertoire was reduced in the ancestor of Olfactores before reexpansion by whole genome duplications in vertebrates
- 2022
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:12
-
Tidskriftsartikel (refereegranskat)abstract
- Cyclic nucleotide-gated (CNG) cation channels are important heterotetrameric proteins in the retina, with different subunit composition in cone and rod photoreceptor cells: three CNGA3 and one CNGB3 in cones and three CNGA1 and one CNGB1 in rods. CNGA and CNGB subunits form separate subfamilies. We have analyzed the evolution of the CNG gene family in metazoans, with special focus on vertebrates by using sequence-based phylogeny and conservation of chromosomal synteny to deduce paralogons resulting from the early vertebrate whole genome duplications (WGDs). Our analyses show, unexpectedly, that the CNGA subfamily had four sister subfamilies in the ancestor of bilaterians and cnidarians that we named CNGC, CNGD, CNGE and CNGF. Of these, CNGC, CNGE and CNGF were lost in the ancestor of Olfactores while CNGD was lost in the vertebrate ancestor. The remaining CNGA and CNGB genes were expanded by a local duplication of CNGA and the subsequent chromosome duplications in the basal vertebrate WGD events. Upon some losses, this resulted in the gnathostome ancestor having three members in the visual CNGA subfamily (CNGA1-3), a single CNGA4 gene, and two members in the CNGB subfamily (CNGB1 and CNGB3). The nature of chromosomal rearrangements in the vertebrate CNGA paralogon was resolved by including the genomes of a non-teleost actinopterygian and an elasmobranch. After the teleost-specific WGD, additional duplicates were generated and retained for CNGA1, CNGA2, CNGA3 and CNGB1. Furthermore, teleosts retain a local duplicate of CNGB3. The retention of duplicated CNG genes is explained by their subfunctionalisation and photoreceptor-specific expression. In conclusion, this study provides evidence for four previously unknown CNG subfamilies in metazoans and further evidence that the early vertebrate WGD events were instrumental in the evolution of the vertebrate visual and central nervous systems.
|
|
| 13. |
- Landin, Jenny, et al.
(författare)
-
Oxytocin Receptors Regulate Social Preference in Zebrafish.
- 2020
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- With a strong tendency to socialise, the zebrafish is a useful model to study social behaviour, with implications for better treatments of social impairments, for instance in autism spectrum disorders. Although oxytocin is crucial for social behaviour in mammals, the importance of the fish orthologue - isotocin or zebrafish oxytocin (zOT) - for social behaviour in zebrafish is unclear. The aims of this study were firstly, to elucidate the receptor specificity of zOT and the related vasotocin or zebrafish vasopressin (zVP; the orthologue of mammalian vasopressin) and the nonpeptidergic oxytocin receptor antagonist L-368,899, and secondly to investigate if L-368,899 inhibits social preference in zebrafish. The potencies of ligands were evaluated for zOT/zVP family receptors in HEK293 cells. Adult and larval zebrafish were treated with L-368,899 or vehicle and subsequently assessed for social behaviour and anxiety (adults only). The antagonist L-368,899 specifically inhibited the two zOT receptors, but not the two zVP-1 receptors. The antagonist decreased social preference in adult and larval zebrafish. It did not affect anxiety in adults. These results indicate that endogenous zOT, and possibly zVP, is involved in social behaviour in zebrafish via either or both of the two zOT receptors, and show promise for future explorations of the anatomy and evolution of networks underlying social behaviour.
|
|
| 14. |
- Larhammar, Dan, 1956-, et al.
(författare)
-
Ancestral vertebrate complexity of the opioid system
- 2015
-
Ingår i: Nociceptin Opioid. - : Academic Press. - 9780128024430
-
Bokkapitel (refereegranskat)abstract
- The evolution of the opioid peptides and nociceptin/orphanin as well as their receptors has been difficult to resolve due to variable evolutionary rates. By combining sequence comparisons with information on the chromosomal locations of the genes, we have deduced the following evolutionary scenario: The vertebrate predecessor had one opi- oid precursor gene and one receptor gene. The two genome doublings before the ver- tebrate radiation resulted in three peptide precursor genes whereupon a fourth copy arose by a local gene duplication. These four precursors diverged to become the pre- propeptides for endorphin (POMC), enkephalins, dynorphins, and nociceptin, respec- tively. The ancestral receptor gene was quadrupled in the genome doublings leading to delta, kappa, and mu and the nociceptin/orphanin receptor. This scenario is corroborated by new data presented here for coelacanth and spotted gar, rep- resenting two basal branches in the vertebrate tree. A third genome doubling in the ancestor of teleost fishes generated additional gene copies. These results show that the opioid system was quite complex already in the first vertebrates and that it has more components in teleost fishes than in mammals. From an evolutionary point of view, nociceptin and its receptor can be considered full-fledged members of the opioid system.
|
|
| 15. |
- Larhammar, Dan, 1956-, et al.
(författare)
-
Evolution of the opioid system.
- 2013. - 2nd
-
Ingår i: Handbook of Biologically Active Peptides. - : Academic Press. - 9780123850959 ; , s. 1562-1569
-
Bokkapitel (refereegranskat)
|
|
| 16. |
- Larhammar, Dan, 1956-, et al.
(författare)
-
Evolution of vertebrate rod and cone phototransduction genes
- 2009
-
Ingår i: Philosophical Transactions of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8436 .- 1471-2970. ; 364:1531, s. 2867-2880
-
Forskningsöversikt (refereegranskat)abstract
- Vertebrate cones and rods in several cases use separate but related components for their signal transduction (opsins, G-proteins, ion channels, etc.). Some of these proteins are also used differentially in other cell types in the retina. Because cones, rods and other retinal cell types originated in early vertebrate evolution, it is of interest to see if their specific genes arose in the extensive gene duplications that took place in the ancestor of the jawed vertebrates (gnathostomes) by two tetraploidizations (genome doublings). The ancestor of teleost fishes subsequently underwent a third tetraploidization. Our previously reported analyses showed that several gene families in the vertebrate visual phototransduction cascade received new members in the basal tetraploidizations. We here expand these data with studies of additional gene families and vertebrate species. We conclude that no less than 10 of the 13 studied phototransduction gene families received additional members in the two basal vertebrate tetraploidizations. Also the remaining three families seem to have undergone duplications during the same time period but it is unclear if this happened as a result of the tetraploidizations. The implications of the many early vertebrate gene duplications for functional specialization of specific retinal cell types, particularly cones and rods, are discussed.
|
|
| 17. |
- Larhammar, Dan, 1956-
(författare)
-
Mystikens neurobiologi och helandets mystik
- 2013
-
Ingår i: Mystik och andlighet - kritiska perspektiv. - Stockholm : Dialogos Förlag. - 9789175042596 ; , s. 199-215
-
Bokkapitel (populärvet., debatt m.m.)
|
|
| 18. |
- Larhammar, Dan, 1956-, et al.
(författare)
-
Tacka dna-explosionen för att du finns
- 2012
-
Ingår i: Forskning & Framsteg. - Stockholm. - 0015-7937. ; 47:9, s. 34-37
-
Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Vid några avgörande ögonblick för ungefär en halv miljard år sedan fick våra föregångare plötsligt massor av nya gener. Spåren syns fortfarande tydligt i vår arvsmassa.
|
|
| 19. |
- Leprince, Jérôme, et al.
(författare)
-
The Arg-Phe-amide peptide 26RFa/glutamine RF-amide peptide and its receptor : IUPHAR Review 24
- 2017
-
Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 174:20, s. 3573-3607
-
Forskningsöversikt (refereegranskat)abstract
- The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross-reactivity with antibodies raised against bovine neuropeptide FF (NPFF). 26RFa and its N-terminally extended form glutamine RF-amide peptide (QRFP) have been identified as cognate ligands of the former orphan receptor GPR103, now renamed glutamine RF-amide peptide receptor (QRFP receptor). The 26RFa/QRFP precursor has been characterized in various mammalian and non-mammalian species. In the brain of mammals, including humans, 26RFa/QRFP mRNA is almost exclusively expressed in hypothalamic nuclei. The 26RFa/QRFP transcript is also present in various organs especially in endocrine glands. While humans express only one QRFP receptor, two isoforms are present in rodents. The QRFP receptor genes are widely expressed in the CNS and in peripheral tissues, notably in bone, heart, kidney, pancreas and testis. Structure-activity relationship studies have led to the identification of low MW peptidergic agonists and antagonists of QRFP receptor. Concurrently, several selective non-peptidic antagonists have been designed from high-throughput screening hit optimization. Consistent with the widespread distribution of QRFP receptor mRNA and 26RFa binding sites, 26RFa/QRFP exerts a large range of biological activities, notably in the control of energy homeostasis, bone formation and nociception that are mediated by QRFP receptor or NPFF2. The present report reviews the current knowledge concerning the 26RFa/QRFP-QRFP receptor system and discusses the potential use of selective QRFP receptor ligands for therapeutic applications.
|
|
| 20. |
- Li, Yanying, et al.
(författare)
-
A D-peptide ligand of neuropeptide Y receptor Y-1 serves as nanocarrier traversing of the blood brain barrier and targets glioma
- 2022
-
Ingår i: Nano Today. - : Elsevier. - 1748-0132 .- 1878-044X. ; 44
-
Tidskriftsartikel (refereegranskat)abstract
- Diseases of the central nervous system (CNS) are challenging for drug treatment because the blood-brain barrier (BBB) restricts entry of drugs into the brain tissue. Therefore, strategies for drug transport across the BBB are an important component in development of CNS drug therapies. Here, a D-amino acid ligand of the neuropeptide Y (NPY) receptor Y1 is described, (D)[Asn(28), Pro(30), Trp(32)]-DNPY (25-36) (termed DAPT), with 2.5 times higher number of hydrogen bonds interacting with the receptor, based on docking into a structural model, than the corresponding peptide with standard L-amino acids (LAPT). Using in vitro BBB models, in vivo healthy mice with intact BBB, and U87-MG orthotopic tumor-bearing mice, we demonstrate that DAPT exhibits significantly higher ability than LAPT to serve as nanocarrier across the BBB and specifically targets gliomas. Using DAPT nanomicelles loaded with IRDye780, it was possible to achieve excellent photothermal therapeutic and photoacoustic cancer imaging. Thus, this study demonstrates the importance of ligand stability and affinity in Y1 receptor-mediated transcytosis and paves the way for versatile brain tumor imaging and therapy using nanomicelles.
|
|
| 21. |
- Ma, Haisha, et al.
(författare)
-
The Neuropeptide Y Y-2 Receptor Is Coexpressed with Nppb in Primary Afferent Neurons and Y-2 Activation Reduces Histaminergic and IL-31-Induced Itch
- 2020
-
Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS. - 0022-3565 .- 1521-0103. ; 372:1, s. 73-82
-
Tidskriftsartikel (refereegranskat)abstract
- Itch stimuli are detected by specialized primary afferents that convey the signal to the spinal cord, but how itch transmission is regulated is still not completely known. Here, we investigated the roles of the neuropeptide Y (NPY)/Y-2 receptor system on scratch behavior. The inhibitory Y-2 receptor is expressed on mouse primary afferents, and intrathecal administration of the Y-2 agonist peptide YY (PYY)(3-36) reduced scratch episode frequency and duration induced by compound 48/80, an effect that could be reversed by intrathecal preadministration of the Y-2 antagonist BIIE0246. Also, scratch episode duration induced by histamine could be reduced by PYY3-36. In contrast, scratch behavior induced by alpha-methyl-5HT, protease-activated receptor-2-activating peptide SLIGRL, chloroquine, topical dust mite extract, or mechanical itch induced by von Frey filaments was unaffected by stimulation of Y2. Primary afferent neurons expressing the Npy2r gene were found to coexpress itch-associated markers such as natriuretic peptide precursor b, oncostatin M receptor, and interleukin (IL) 31 receptor A. Accordingly, intrathecal PYY3-36 reduced the scratch behavior induced by IL-31. Our findings imply that the NPY/Y-2 system reduces histaminergic and IL-31-associated itch through presynaptic inhibition of a subpopulation of itch-associated primary afferents. SIGNIFICANCE STATEMENT The spinal neuropeptide Y system dampens scratching behavior induced by histaminergic compounds and interleukin 31, a cytokine involved in atopic dermatitis, through interactions with the Y-2 receptor. The Y-2 receptor is expressed by primary afferent neurons that are rich in itch-associated neurotransmitters and receptors such as somatostatin, natriuretic peptide precursor b, and interleukin 31 receptors.
|
|
| 22. |
- Morini, Marina, et al.
(författare)
-
Dynamic evolution of transient receptor potential vanilloid (TRPV) ion channel family with numerous gene duplications and losses
- 2022
-
Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- The transient receptor potential vanilloid (TRPV) ion channel family is involved in multiple sensory and physiological functions including thermosensing and temperature-dependent neuroendocrine regulation. The objective of the present study was to investigate the number, origin and evolution of TRPV genes in metazoans, with special focus on the impact of the vertebrate whole-genome duplications (WGD). Gene searches followed by phylogenetic and synteny analyses revealed multiple previously undescribed TRPV genes. The common ancestor of Cnidaria and Bilateria had three TRPV genes that became four in the deuterostome ancestor. Two of these were lost in the vertebrate ancestor. The remaining two genes gave rise to two TRPV subfamilies in vertebrates, consisting of subtypes 1, 2, 3, 4, 9 and 5, 6, 7, 8, respectively. This gene expansion resulted from the two basal vertebrate WGD events (1R and 2R) and three local duplications before the radiation of gnathostomes. TRPV1, 4 and 5 have been retained in all gnathostomes investigated, presumably reflecting important functions. TRPV7 and 8 have been lost independently in various lineages but are still retained in cyclostomes, actinistians (coelacanth), amphibians, prototherians and basal actinopterygians (Polypteridae). TRPV3 and 9 are present in extant elasmobranchs, while TRPV9 was lost in the osteichthyan ancestor and TRPV3 in the actinopterygian ancestor. The coelacanth has retained the ancestral osteichthyan repertoire of TRPV1, 3, 4, 5, 7 and 8. TRPV2 arose in the tetrapod ancestor. Duplications of TRPV5 occurred independently in various lineages, such as cyclostomes, chondrichthyans, anuran amphibians, sauropsids, mammals (where the duplicate is called TRPV6), and actinopterygians (Polypteridae and Esocidae). After the teleost-specific WGD (3R) only TRPV1 retained its duplicate, whereas TRPV4 and 5 remained as single genes. Both 3R-paralogs of TRPV1 were kept in some teleost species, while one paralog was lost in others. The salmonid-specific WGD (4R) duplicated TRPV1, 4, and 5 leading to six TRPV genes. The largest number was found in Xenopus tropicalis with no less than 15 TRPV genes. This study provides a comprehensive evolutionary scenario for the vertebrate TRPV family, revealing additional TRPV types and proposing a phylogeny-based classification of TRPV across metazoans.
|
|
| 23. |
- Ocampo Daza, Daniel, 1984-, et al.
(författare)
-
Evolution of the growth hormone, prolactin, prolactin 2 and somatolactin family
- 2018
-
Ingår i: General and Comparative Endocrinology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0016-6480 .- 1095-6840. ; 264, s. 94-112
-
Tidskriftsartikel (refereegranskat)abstract
- Growth hormone (GH), prolactin (PRL), prolactin 2 (PRL2) and somatolactin (SL) belong to the same hormone family and have a wide repertoire of effects including development, osmoregulation, metabolism and stimulation of growth. Both the hormone and the receptor family have been proposed to have expanded by gene duplications in early vertebrate evolution. A key question is how hormone-receptor preferences have arisen among the duplicates. The first step to address this is to determine the time window for these duplications. Specifically, we aimed to see if duplications resulted from the two basal vertebrate tetraploidizations (1R and 2R). GH family genes from a broad range of vertebrate genomes were investigated using a combination of sequence-based phylogenetic analyses and comparisons of synteny. We conclude that the PRL and PRL2 genes arose from a common ancestor in 1R/2R, as shown by neighboring gene families. No other gene duplicates were preserved from these tetraploidization events. The ancestral genes that would give rise to GH and PRL/PRL2 arose from an earlier duplication; most likely a local gene duplication as they are syntenic in several species. Likewise, some evidence suggests that SL arose from a local duplication of an ancestral GH/SL gene in the same time window, explaining the lack of similarity in chromosomal neighbors to GH, PRL or PRL2. Thus, the basic triplet of ancestral GH, PRL/ PRL2 and SL genes appear to be unexpectedly ancient. Following 1R/2R, only SL was duplicated in the teleost-specific tetraploidization 3R, resulting in SLa and SLb. These time windows contrast with our recent report that the corresponding receptor genes GHR and PRLR arose through a local duplication in jawed vertebrates and that both receptor genes duplicated further in 3R, which reveals a surprising asynchrony in hormone and receptor gene duplications.
|
|
| 24. |
- Ocampo Daza, Daniel, 1984-, et al.
(författare)
-
Evolution of the receptors for growth hormone, prolactin, erythropoietin and thrombopoietin in relation to the vertebrate tetraploidizations
- 2018
-
Ingår i: General and Comparative Endocrinology. - : Elsevier BV. - 0016-6480 .- 1095-6840. ; 257, s. 143-160
-
Tidskriftsartikel (refereegranskat)abstract
- The receptors for the pituitary hormones growth hormone (GH), prolactin (PRL) and somatolactin (SL), and the hematopoietic hormones erythropoietin (EPO) and thrombopoietin (TPO), comprise a structurally related family in the superfamily of cytokine class-I receptors. GH, PRL and SL receptors have a wide variety of effects in development, osmoregulation, metabolism and stimulation of growth, while EPO and TPO receptors guide the production and differentiation of erythrocytes and thrombocytes, respectively. The evolution of the receptors for GH, PRL and SL has been partially investigated by previous reports suggesting different time points for the hormone and receptor gene duplications. This raises questions about how hormone-receptor partnerships have emerged and evolved. Therefore, we have investigated in detail the expansion of this receptor family, especially in relation to the basal vertebrate (1R, 2R) and teleost (3R) tetraploidizations. Receptor family genes were identified in a broad range of vertebrate genomes and investigated using a combination of sequence-based phylogenetic analyses and comparative genomic analyses of synteny. We found that 1R most likely generated EPOR/TPOR and GHR/PRLR ancestors; following this, 2R resulted in EPOR and TPOR genes. No GHR/PRLR duplicate seems to have survived after 2R. Instead the single GHR/PRLR underwent a local duplication sometime after 2R, generating separate syntenic genes for GHR and PRLR. Subsequently, 3R duplicated the gene pair in teleosts, resulting in two GHR and two PRLR genes, but no EPOR or TPOR duplicates. These analyses help illuminate the evolution of the regulatory mechanisms for somatic growth, metabolism, osmoregulation and hematopoiesis in vertebrates.
|
|
| 25. |
- Ocampo Daza, Daniel, et al.
(författare)
-
The Evolution of Oxytocin and Vasotocin Receptor Genes in Jawed Vertebrates : A Clear Case for Gene Duplications Through Ancestral Whole-Genome Duplications
- 2022
-
Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- The neuronal and neuroendocrine peptides oxytocin (OT) and vasotocin (VT), including vasopressins, have six cognate receptors encoded by six receptor subtype genes in jawed vertebrates. The peptides elicit a broad range of responses that are specifically mediated by the receptor subtypes including neuronal functions regulating behavior and hormonal actions on reproduction and water/electrolyte balance. Previously, we have demonstrated that these six receptor subtype genes, which we designated VTR1A, VTR1B, OTR, VTR2A, VTR2B and VTR2C, arose from a syntenic ancestral gene pair, one VTR1/OTR ancestor and one VTR2 ancestor, through the early vertebrate whole-genome duplications (WGD) called 1R and 2R. This was supported by both phylogenetic and chromosomal conserved synteny data. More recently, other studies have focused on confounding factors, such as the OTR/VTR orthologs in cyclostomes, to question this scenario for the origin of the OTR/VTR gene family; proposing instead less parsimonious interpretations involving only one WGD followed by complex series of chromosomal or segmental duplications. Here, we have updated the phylogeny of the OTR/VTR gene family, including a larger number of vertebrate species, and revisited seven representative neighboring gene families from our previous conserved synteny analyses, adding chromosomal information from newer high-coverage genome assemblies from species that occupy key phylogenetic positions: the polypteriform fish reedfish (Erpetoichthys calabaricus), the cartilaginous fish thorny skate (Amblyraja radiata) and a more recent high-quality assembly of the Western clawed frog (Xenopus tropicalis) genome. Our analyses once again add strong support for four-fold symmetry, i.e., chromosome quadruplication in the same time window as the WGD events early in vertebrate evolution, prior to the jawed vertebrate radiation. Thus, the evolution of the OTR/VTR gene family can be most parsimoniously explained by two WGD events giving rise to the six ancestral genes, followed by differential gene losses of VTR2 genes in different lineages. We also argue for more coherence and clarity in the nomenclature of OT/VT receptors, based on the most parsimonious scenario.
|
|
