The PLC/IP3R/PKC pathway is required for ethanol-enhanced GABA release

NEUROPHARMACOLOGY

卷:58

Article

Kelm, M. Katherine^1,5  Weinberg, Richard J.^3,4  Criswell, Hugh E.^2,5  Breese, George R.^1,2,4,5 

[1] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Sch Med, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA

[4] Univ N Carolina, Sch Med, Ctr Neurosci, Chapel Hill, NC 27599 USA

[5] Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA

关键词: Ethanol;    gamma-Aminobutyric acid;    Miniature inhibitory postsynaptic currents;    Phospholipase C;    Protein kinase C;    Inositol 1,4,5-trisphosphate receptors;   

DOI  :  10.1016/j.neuropharm.2010.02.018

来源: Elsevier

【 摘 要 】

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 IP3, 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 IP3R 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/IP3R/PKC pathway is necessary for ethanol to increase spontaneous GABA release from presynaptic terminals onto Purkinje cells. Published by Elsevier Ltd.

【 授权许可】

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