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The Journal of Neuroscience, April 6, 2005, 25(14):3571-3577; doi:10.1523/JNEUROSCI.4971-04.2005

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Cellular/Molecular
Selective Modulation of Neuronal Nicotinic Acetylcholine Receptor Channel Subunits by G_o-Protein Subunits

Harald Fischer, Dong-Mei Liu, Aven Lee, Janet C. Harries, and David J. Adams

School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia

G-protein modulation of neuronal nicotinic acetylcholine receptor (nAChR) channels in rat intrinsic cardiac ganglia was examined using dialyzed whole-cell and excised membrane patch-recording configurations. Cell dialysis with GTPS increased the agonist affinity of nAChRs, resulting in a potentiation of nicotine-evoked whole-cell currents at low concentrations. ACh- and nicotine-evoked current amplitudes were increased approximately twofold in the presence of GTPS. In inside-out membrane patches, the open probability (NP_o) of nAChR-mediated unitary currents was reversibly increased fourfold after bath application of 0.2 mM GTPS relative to control but was unchanged in the presence of GDPS. The modulation of nAChR-mediated whole-cell currents was agonist specific; currents evoked by the cholinergic agonists ACh, nicotine, and 1,1-dimethyl-4-phenylpiperazinium iodide, but not cytisine or choline, were potentiated in the presence of GTPS. The direct interaction between G-protein subunits and nAChRs was examined by bath application of either G_o or G subunits to inside-out membrane patches and in glutathione S-transferase pull-down and coimmunoprecipitation experiments. Bath application of 50 nM G increased the open probability of ACh-activated single-channel currents fivefold, whereas G_o (50 nM) produced no significant increase in NP_o. Neuronal nAChR subunits 3-5 and 2 exhibited a positive interaction with G_o and G, whereas 4 and 7 failed to interact with either of the G-protein subunits. These results provide evidence for a direct interaction between nAChR and G-protein subunits, underlying the increased open probability of ACh-activated single-channel currents and potentiation of nAChR-mediated whole-cell currents in parasympathetic neurons of rat intrinsic cardiac ganglia.

Key words: cholinergic; nicotinic receptor; G-protein subunits; parasympathetic; intracardiac ganglia; patch clamp

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Received Aug 26, 2004; revised February 21, 2005; accepted February 22, 2005.

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