Cyclic AMP‐dependent protein kinase and D1 dopamine receptors regulate diacylglycerol lipase‐α and synaptic 2‐arachidonoyl glycerol signaling
| Autor: | Christian R. Marks, Brian C. Shonesy, Jason R. Stephenson, Roger J. Colbran |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Diacylglycerol lipase Cannabinoid receptor Mice Transgenic Arachidonic Acids Medium spiny neuron Biochemistry Article Glycerides Mice 03 medical and health sciences Cellular and Molecular Neuroscience Organ Culture Techniques 0302 clinical medicine Animals Humans Protein phosphorylation Protein kinase A Dose-Response Relationship Drug biology Chemistry Receptors Dopamine D1 Brain Cyclic AMP-Dependent Protein Kinases Endocannabinoid system Cell biology Mice Inbred C57BL Lipoprotein Lipase HEK293 Cells 030104 developmental biology Metabotropic glutamate receptor Dopamine Agonists biology.protein Dopamine Antagonists Phosphorylation 030217 neurology & neurosurgery Endocannabinoids Signal Transduction |
| Zdroj: | J Neurochem |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1111/jnc.14972 |
| Popis: | Brain endocannabinoids serve as retrograde neurotransmitters, being synthesized in post-synaptic neurons "on demand" and released to bind pre-synaptic cannabinoid receptors and suppress glutamatergic or GABAergic transmission. The most abundant brain endocannabinoid, 2 arachidonoyl glycerol (2-AG), is primarily synthesized by diacylglycerol lipase-α (DGLα), which is activated by poorly understood mechanisms in response to calcium influx following post-synaptic depolarization and/or the activation of Gq -coupled group 1 metabotropic glutamate receptors. However, the impact of other neurotransmitters and their downstream signaling pathways on synaptic 2-AG signaling has not been intensively studied. Here, we found that DGLα activity in membrane fractions from transfected HEK293T cells was significantly increased by in vitro phosphorylation using cyclic AMP-dependent protein kinase (PKA). Moreover, PKA directly phosphorylated DGLα at Ser798 in vitro. Elevation of cAMP levels in HEK293 cells expressing DGLα increased Ser798 phosphorylation, as detected using a phospho-Ser798-specific antibody, and enhanced DGLα activity; this in situ enhancement of DGLα activity was prevented by mutation of Ser798 to Ala. We investigated the impact of PKA on synaptic 2-AG mobilization in mouse striatal slices by manipulating D1-dopamine receptor (D1R) signaling and assessing depolarization-induced suppression of excitation, a DGLα- and 2-AG-dependent form of short-term synaptic depression. The magnitude of depolarization-enhanced suppression of excitation in direct pathway medium spiny neurons was increased by pre-incubation with a D1R agonist, and this enhancement was blocked by post-synaptic inhibition of PKA. Taken together, these findings provide new molecular insights into the complex mechanisms regulating synaptic endocannabinoid signaling. |
| Databáze: | OpenAIRE |
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