Muscarinic M2 and M1 receptors reduce GABA release by Ca2%2b channel modulation through activation of PI3K/ Ca2%2b-independent and PLC/Ca2%2b-dependent PKC Article uri icon

abstract

  • We measured pharmacologically isolated GABAergic currents from layer II/III neurons of the rat auditory cortex using patch-clamp recording. Activation of muscarinic receptors by muscarine (1 μM) or oxotremorine (10 μM) decreased the amplitude of electrically evoked inhibitory postsynaptic currents to about one third of their control value. Neither miniature nor exogenously evoked GABAergic currents were altered by the presence of muscarinic agonists, indicating that the effect was spike-dependent and not mediated postsynaptically. The presence of the N- or P/Q-type Ca2%2b channel blockers ω-conotoxin GVIA (1 μM) or ω-AgaTx TK (200 nM) greatly blocked the muscarinic effect, suggesting that Ca2%2b-channels were target of the muscarinic modulation. The presence of the muscarinic M 2 receptor (M2R) antagonists methoctramine (5 μM) or AF-DX 116 (1 μM) blocked most of the muscarinic evoked inhibitory postsynaptic current (eIPSC) reduction, indicating that M2Rs were responsible for the effect, whereas the remaining component of the depression displayed M1R-like sensitivity. Tissue preincubation with the specific blockers of phosphatidyl-inositol-3-kinase (PI3K) wortmannin (200 nM), LY294002 (1 μM), or with the Ca2%2b-dependent PKC inhibitor Gö 6976 (200 nM) greatly impaired the muscarinic decrease of the eIPSC amplitude, whereas the remaining component was sensitive to preincubation in the phospholipase C blocker U73122 (10 μM). We conclude that acetylcholine release enhances the excitability of the auditory cortex by decreasing the release of GABA by inhibiting axonal V-dependent Ca2%2b channels, mostly through activation of presynaptic M2Rs/PI3K/Ca 2%2b-independent PKC pathway and - to a smaller extent - by the activation of M1/PLC/Ca2%2b-dependent PKC. Copyright © 2007 The American Physiological Society.

publication date

  • 2007-01-01