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The PLC/IP 3 R/PKC pathway is required for ethanol-enhanced GABA release.
Neuropharmacology. 2010 Jun; 58(7):1179-86.N

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7365, USA. katie_kelm@unc.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20206640

Citation

Kelm, M Katherine, et al. "The PLC/IP 3 R/PKC Pathway Is Required for Ethanol-enhanced GABA Release." Neuropharmacology, vol. 58, no. 7, 2010, pp. 1179-86.
Kelm MK, Weinberg RJ, Criswell HE, et al. The PLC/IP 3 R/PKC pathway is required for ethanol-enhanced GABA release. Neuropharmacology. 2010;58(7):1179-86.
Kelm, M. K., Weinberg, R. J., Criswell, H. E., & Breese, G. R. (2010). The PLC/IP 3 R/PKC pathway is required for ethanol-enhanced GABA release. Neuropharmacology, 58(7), 1179-86. https://doi.org/10.1016/j.neuropharm.2010.02.018
Kelm MK, et al. The PLC/IP 3 R/PKC Pathway Is Required for Ethanol-enhanced GABA Release. Neuropharmacology. 2010;58(7):1179-86. PubMed PMID: 20206640.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The PLC/IP 3 R/PKC pathway is required for ethanol-enhanced GABA release. AU - Kelm,M Katherine, AU - Weinberg,Richard J, AU - Criswell,Hugh E, AU - Breese,George R, Y1 - 2010/03/04/ PY - 2009/12/16/received PY - 2010/02/23/revised PY - 2010/02/24/accepted PY - 2010/3/9/entrez PY - 2010/3/9/pubmed PY - 2010/7/20/medline SP - 1179 EP - 86 JF - Neuropharmacology JO - Neuropharmacology VL - 58 IS - 7 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/20206640/The_PLC/IP_3_R/PKC_pathway_is_required_for_ethanol_enhanced_GABA_release_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(10)00064-X DB - PRIME DP - Unbound Medicine ER -