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The role of protein kinase A in the ethanol-induced increase in spontaneous GABA release onto cerebellar Purkinje neurons.
J Neurophysiol. 2008 Dec; 100(6):3417-28.JN

Abstract

Ethanol increases miniature inhibitory postsynaptic current frequency and decreases the paired-pulse ratio, which suggests that ethanol increases both spontaneous and evoked GABA release, respectively. We have shown previously that ethanol increases GABA release at the rat interneuron-Purkinje cell synapse and that this ethanol effect involves calcium release from internal stores; however, further exploration of the mechanism responsible for ethanol-enhanced GABA release was needed. We found that a cannabinoid receptor 1 (CB1) agonist, WIN-55212, and a GABA(B) receptor agonist, baclofen, decreased baseline spontaneous GABA release and prevented ethanol from increasing spontaneous GABA release. The CB1 receptor and GABA(B) receptor are Galpha i-linked G protein-coupled receptors with common downstream messengers that include adenylate cyclase and protein kinase A (PKA). Adenylate cyclase and PKA antagonists blocked ethanol from increasing spontaneous GABA release, whereas a PKA antagonist limited to the postsynaptic neuron did not block ethanol from increasing spontaneous GABA release. These results suggest that presynaptic PKA plays an essential role in ethanol-enhanced spontaneous GABA release. Similar to ethanol, we found that the mechanism of the cannabinoid-mediated decrease in spontaneous GABA release involves internal calcium stores and PKA. A PKA antagonist decreased baseline spontaneous GABA release. This effect was reduced after incubating the slice with a calcium chelator, BAPTA-AM, but was unaffected when BAPTA was limited to the postsynaptic neuron. This suggests that the PKA antagonist is acting through a presynaptic, calcium-dependent mechanism to decrease spontaneous GABA release. Overall, these results suggest that PKA activation is necessary for ethanol to increase spontaneous GABA release.

Authors+Show Affiliations

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA. katie_kelm@med.unc.eduNo 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

18945815

Citation

Kelm, M Katherine, et al. "The Role of Protein Kinase a in the Ethanol-induced Increase in Spontaneous GABA Release Onto Cerebellar Purkinje Neurons." Journal of Neurophysiology, vol. 100, no. 6, 2008, pp. 3417-28.
Kelm MK, Criswell HE, Breese GR. The role of protein kinase A in the ethanol-induced increase in spontaneous GABA release onto cerebellar Purkinje neurons. J Neurophysiol. 2008;100(6):3417-28.
Kelm, M. K., Criswell, H. E., & Breese, G. R. (2008). The role of protein kinase A in the ethanol-induced increase in spontaneous GABA release onto cerebellar Purkinje neurons. Journal of Neurophysiology, 100(6), 3417-28. https://doi.org/10.1152/jn.90970.2008
Kelm MK, Criswell HE, Breese GR. The Role of Protein Kinase a in the Ethanol-induced Increase in Spontaneous GABA Release Onto Cerebellar Purkinje Neurons. J Neurophysiol. 2008;100(6):3417-28. PubMed PMID: 18945815.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The role of protein kinase A in the ethanol-induced increase in spontaneous GABA release onto cerebellar Purkinje neurons. AU - Kelm,M Katherine, AU - Criswell,Hugh E, AU - Breese,George R, Y1 - 2008/10/22/ PY - 2008/10/24/pubmed PY - 2009/4/25/medline PY - 2008/10/24/entrez SP - 3417 EP - 28 JF - Journal of neurophysiology JO - J Neurophysiol VL - 100 IS - 6 N2 - Ethanol increases miniature inhibitory postsynaptic current frequency and decreases the paired-pulse ratio, which suggests that ethanol increases both spontaneous and evoked GABA release, respectively. We have shown previously that ethanol increases GABA release at the rat interneuron-Purkinje cell synapse and that this ethanol effect involves calcium release from internal stores; however, further exploration of the mechanism responsible for ethanol-enhanced GABA release was needed. We found that a cannabinoid receptor 1 (CB1) agonist, WIN-55212, and a GABA(B) receptor agonist, baclofen, decreased baseline spontaneous GABA release and prevented ethanol from increasing spontaneous GABA release. The CB1 receptor and GABA(B) receptor are Galpha i-linked G protein-coupled receptors with common downstream messengers that include adenylate cyclase and protein kinase A (PKA). Adenylate cyclase and PKA antagonists blocked ethanol from increasing spontaneous GABA release, whereas a PKA antagonist limited to the postsynaptic neuron did not block ethanol from increasing spontaneous GABA release. These results suggest that presynaptic PKA plays an essential role in ethanol-enhanced spontaneous GABA release. Similar to ethanol, we found that the mechanism of the cannabinoid-mediated decrease in spontaneous GABA release involves internal calcium stores and PKA. A PKA antagonist decreased baseline spontaneous GABA release. This effect was reduced after incubating the slice with a calcium chelator, BAPTA-AM, but was unaffected when BAPTA was limited to the postsynaptic neuron. This suggests that the PKA antagonist is acting through a presynaptic, calcium-dependent mechanism to decrease spontaneous GABA release. Overall, these results suggest that PKA activation is necessary for ethanol to increase spontaneous GABA release. SN - 0022-3077 UR - https://www.unboundmedicine.com/medline/citation/18945815/The_role_of_protein_kinase_A_in_the_ethanol_induced_increase_in_spontaneous_GABA_release_onto_cerebellar_Purkinje_neurons_ L2 - https://journals.physiology.org/doi/10.1152/jn.90970.2008?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -