Tags

Type your tag names separated by a space and hit enter

Mechanism of GABA receptor-mediated inhibition of spontaneous GABA release onto cerebellar Purkinje cells.
Eur J Neurosci. 2004 Aug; 20(3):684-700.EJ

Abstract

gamma-Aminobutyric acid (GABA)(B) receptor-mediated modulation of spontaneous GABA release onto Purkinje cells was investigated in cerebellar slices from 3- to 5-week-old mice. The GABA(B) receptor agonists baclofen and CGP 44533 each reduced the frequency of miniature inhibitory postsynaptic currents (mIPSCs), with no significant effect on mIPSC amplitude; together, consistent with a presynaptic site of action. The GABA(B) receptor antagonist CGP 55845 blocked baclofen-induced inhibition. The sulphydryl alkylating agent N-ethylmaleimide occluded baclofen effects, implicating G(i/o) subunits in mediating a GABA(B) G protein-coupled receptor pathway. Baclofen-induced inhibition persisted in the presence of Ba(2+), a blocker of K(+) channels, and Cd(2+), a blocker of Ca(2+) channel-mediated GABA release. Application of nominally Ca(2+)-free extracellular solutions reduced mIPSC frequency and amplitude; however, baclofen produced a significant inhibition in mIPSC frequency, further suggesting that this pathway was independent of Ca(2+) influx. Spontaneous GABA release was increased by the adenylate cyclase activator, forskolin, and the phorbol ester, phorbol 12,13-dibutyrate. However, baclofen-induced inhibition was not significantly changed in either condition. Baclofen action was also not affected by the adenylate cyclase inhibitor SQ 22536 or the protein kinase C inhibitor chelerythrine chloride. Baclofen still reduced mIPSC frequency in the presence of the polyvalent cation ruthenium red, which acts as a secretagogue here; however, baclofen-induced inhibition was reduced significantly. Furthermore, baclofen produced no clear inhibition during high-frequency mIPSCs bursts induced by the potent secretagogue alpha-Latrotoxin. Together, these results suggest that GABA(B) inhibition occurs downstream of Ca(2+) influx and may be mediated, in part, by an inhibition of the vesicular release mechanism.

Authors+Show Affiliations

Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.No affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15255979

Citation

Harvey, Victoria L., and Gary J. Stephens. "Mechanism of GABA Receptor-mediated Inhibition of Spontaneous GABA Release Onto Cerebellar Purkinje Cells." The European Journal of Neuroscience, vol. 20, no. 3, 2004, pp. 684-700.
Harvey VL, Stephens GJ. Mechanism of GABA receptor-mediated inhibition of spontaneous GABA release onto cerebellar Purkinje cells. Eur J Neurosci. 2004;20(3):684-700.
Harvey, V. L., & Stephens, G. J. (2004). Mechanism of GABA receptor-mediated inhibition of spontaneous GABA release onto cerebellar Purkinje cells. The European Journal of Neuroscience, 20(3), 684-700.
Harvey VL, Stephens GJ. Mechanism of GABA Receptor-mediated Inhibition of Spontaneous GABA Release Onto Cerebellar Purkinje Cells. Eur J Neurosci. 2004;20(3):684-700. PubMed PMID: 15255979.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism of GABA receptor-mediated inhibition of spontaneous GABA release onto cerebellar Purkinje cells. AU - Harvey,Victoria L, AU - Stephens,Gary J, PY - 2004/7/17/pubmed PY - 2004/9/24/medline PY - 2004/7/17/entrez SP - 684 EP - 700 JF - The European journal of neuroscience JO - Eur J Neurosci VL - 20 IS - 3 N2 - gamma-Aminobutyric acid (GABA)(B) receptor-mediated modulation of spontaneous GABA release onto Purkinje cells was investigated in cerebellar slices from 3- to 5-week-old mice. The GABA(B) receptor agonists baclofen and CGP 44533 each reduced the frequency of miniature inhibitory postsynaptic currents (mIPSCs), with no significant effect on mIPSC amplitude; together, consistent with a presynaptic site of action. The GABA(B) receptor antagonist CGP 55845 blocked baclofen-induced inhibition. The sulphydryl alkylating agent N-ethylmaleimide occluded baclofen effects, implicating G(i/o) subunits in mediating a GABA(B) G protein-coupled receptor pathway. Baclofen-induced inhibition persisted in the presence of Ba(2+), a blocker of K(+) channels, and Cd(2+), a blocker of Ca(2+) channel-mediated GABA release. Application of nominally Ca(2+)-free extracellular solutions reduced mIPSC frequency and amplitude; however, baclofen produced a significant inhibition in mIPSC frequency, further suggesting that this pathway was independent of Ca(2+) influx. Spontaneous GABA release was increased by the adenylate cyclase activator, forskolin, and the phorbol ester, phorbol 12,13-dibutyrate. However, baclofen-induced inhibition was not significantly changed in either condition. Baclofen action was also not affected by the adenylate cyclase inhibitor SQ 22536 or the protein kinase C inhibitor chelerythrine chloride. Baclofen still reduced mIPSC frequency in the presence of the polyvalent cation ruthenium red, which acts as a secretagogue here; however, baclofen-induced inhibition was reduced significantly. Furthermore, baclofen produced no clear inhibition during high-frequency mIPSCs bursts induced by the potent secretagogue alpha-Latrotoxin. Together, these results suggest that GABA(B) inhibition occurs downstream of Ca(2+) influx and may be mediated, in part, by an inhibition of the vesicular release mechanism. SN - 0953-816X UR - https://www.unboundmedicine.com/medline/citation/15255979/Mechanism_of_GABA_receptor_mediated_inhibition_of_spontaneous_GABA_release_onto_cerebellar_Purkinje_cells_ DB - PRIME DP - Unbound Medicine ER -