The PLC/IP3R/PKC pathway is required for ethanol-enhanced GABA release
| Autor: | Hugh E. Criswell, Richard J. Weinberg, M. Katherine Kelm, George R. Breese |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Presynaptic Terminals In Vitro Techniques Biology Article gamma-Aminobutyric acid Diglycerides Rats Sprague-Dawley Synapse Purkinje Cells Cellular and Molecular Neuroscience chemistry.chemical_compound Interneurons Postsynaptic potential Cerebellum medicine Animals Inositol 1 4 5-Trisphosphate Receptors Calphostin Ethanol effect Protein Kinase C gamma-Aminobutyric Acid Protein kinase C Pharmacology Ethanol Phospholipase C Central Nervous System Depressants Rats Cell biology nervous system Biochemistry chemistry Type C Phospholipases GABAergic Calcium Signal Transduction medicine.drug |
| Zdroj: | Neuropharmacology. 58:1179-1186 |
| ISSN: | 0028-3908 |
| Popis: | Research on the actions of ethanol at the GABAergic synapse has traditionally focused on postsynaptic mechanisms, but recent data demonstrate that ethanol also increases both evoked and spontaneous GABA release in many brain regions. Using whole-cell voltage-clamp recordings, we previously showed that ethanol increases spontaneous GABA release at the rat interneuron-Purkinje cell synapse. This presynaptic ethanol effect is dependent on calcium release from internal stores, possibly through activation of inositol 1,4,5-trisphosphate receptors (IP(3)Rs). After confirming that ethanol targets vesicular GABA release, in the present study we used electron microscopic immunohistochemistry to demonstrate that IP(3)Rs are located in presynaptic terminals of cerebellar interneurons. Activation of IP(3)Rs requires binding of IP(3), generated through activation of phospholipase C (PLC). We find that the PLC antagonist edelfosine prevents ethanol from increasing spontaneous GABA release. Diacylglycerol generated by PLC and calcium released by activation of the IP(3)R activate protein kinase C (PKC). Ethanol-enhanced GABA release was blocked by two PKC antagonists, chelerythrine and calphostin C. When a membrane impermeable PKC antagonist, PKC (19-36), was delivered intracellularly to the postsynaptic neuron, ethanol continued to increase spontaneous GABA release. Overall, these results suggest that activation of the PLC/IP(3)R/PKC pathway is necessary for ethanol to increase spontaneous GABA release from presynaptic terminals onto Purkinje cells. |
| Databáze: | OpenAIRE |
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