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Genetic Manipulatio...
Genetic Manipulation of sn-1-Diacylglycerol Lipase and CB1 Cannabinoid Receptor Gain-of-Function Uncover Neuronal 2-Linoleoyl Glycerol Signaling in Drosophila melanogaster
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- Tortoriello, Giuseppe (författare)
- Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden.
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- Beiersdorf, Johannes (författare)
- Med Univ Vienna, Ctr Brain Res, Dept Mol Neurosci, Spitalgasse 4, A-1090 Vienna, Austria.
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- Romani, Susana (författare)
- Kings Coll London, Wolfson Ctr Age Related Dis, London, England.
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visa fler...
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- Williams, Gareth (författare)
- Kings Coll London, Wolfson Ctr Age Related Dis, London, England.
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- Cameron, Gary A. (författare)
- Univ Aberdeen, Sch Appl Med & Dent, Aberdeen, Scotland.
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- Mackie, Ken (författare)
- Indiana Univ, Dept Psychol & Brain Sci, Gill Ctr Biomol Sci, Bloomington, IN USA.
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- Williams, Michael J. (författare)
- Uppsala universitet,Schiöth: Funktionell farmakologi
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- Di Marzo, Vincenzo (författare)
- CNR, Endocannabinoid Res Grp, Ist Chim Biomol, Pozzuoli, Italy.;Univ Laval, Canada Excellence Res Chair, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada.;Univ Laval, Inst Nutr & Aliments Fonct, Quebec City, PQ, Canada.
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- Keimpema, Erik (författare)
- Med Univ Vienna, Ctr Brain Res, Dept Mol Neurosci, Spitalgasse 4, A-1090 Vienna, Austria.
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- Doherty, Patrick (författare)
- Kings Coll London, Wolfson Ctr Age Related Dis, London, England.
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- Harkany, Tibor (författare)
- Karolinska Institutet
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Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden Med Univ Vienna, Ctr Brain Res, Dept Mol Neurosci, Spitalgasse 4, A-1090 Vienna, Austria. (creator_code:org_t)
- Mary Ann Liebert, 2021
- 2021
- Engelska.
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Ingår i: Cannabis and cannabinoid research. - : Mary Ann Liebert. - 2578-5125 .- 2378-8763. ; 6:2, s. 119-136
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Introduction: In mammals, sn-1-diacylglycerol lipases (DAGL) generate 2-arachidonoylglycerol (2-AG) that, as the major endocannabinoid, modulates synaptic neurotransmission by acting on CB1 cannabinoid receptors (CB1R). Even though the insect genome codes for inaE, which is a DAGL ortholog (dDAGL), its products and their functions remain unknown particularly because insects lack chordate-type cannabinoid receptors. Materials and Methods: Gain-of-function and loss-of-function genetic manipulations were carried out in Drosophila melanogaster, including the generation of both dDAGL-deficient and mammalian CB1R-overexpressing flies. Neuroanatomy, dietary manipulations coupled with targeted mass spectrometry determination of arachidonic acid and 2-linoleoyl glycerol (2-LG) production, behavioral assays, and signal transduction profiling for Akt and Erk kinases were employed. Findings from Drosophilae were validated by a CB1R-binding assay for 2-LG in mammalian cortical homogenates with functionality confirmed in neurons using high-throughput real-time imaging in vitro. Results: In this study, we show that dDAGL is primarily expressed in the brain and nerve cord of Drosophila during larval development and in adult with 2-LG being its chief product as defined by dietary precursor availability. Overexpression of the human CB1R in the ventral nerve cord compromised the mobility of adult Drosophilae. The causality of 2-LG signaling to CB1R-induced behavioral impairments was shown by inaE inactivation normalizing defunct motor coordination. The 2-LG-induced activation of transgenic CB(1)Rs affected both Akt and Erk kinase cascades by paradoxical signaling. Data from Drosophila models were substantiated by showing 2-LG-mediated displacement of [H-3]CP 55,940 in mouse cortical homogenates and reduced neurite extension and growth cone collapsing responses in cultured mouse neurons. Conclusions: Overall, these results suggest that 2-LG is an endocannabinoid-like signal lipid produced by dDAGL in Drosophila.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Nyckelord
- 2-monoacylglycerol
- behavior
- development
- diacylglycerol lipase
- inaE
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Tortoriello, Giu ...
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Beiersdorf, Joha ...
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Romani, Susana
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Williams, Gareth
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Cameron, Gary A.
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Mackie, Ken
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visa fler...
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Williams, Michae ...
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Di Marzo, Vincen ...
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Keimpema, Erik
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Doherty, Patrick
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Harkany, Tibor
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Uppsala universitet
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Karolinska Institutet