Muscarinic acetylcholine receptors (mAChRs) are known to mediate the acetylcholine inhibition of Ca2+ channels in central and peripheral neurons. Stellate ganglion (SG) neurons provide the main sympathetic input to the heart and contribute to the regulation of heart rate and myocardial contractility. Little information is available regarding mAChR regulation of Ca2+ channels in SG neurons. The purpose of this study was to identify the mAChR subtypes that modulate Ca2+ channel currents in rat SG neurons innervating heart muscle. Accordingly, the modulation of Ca 2+ channel currents by the muscarinic cholinergic agonist, oxotremorine-methiodide (Oxo-M), and mAChR blockers was examined. Oxo-M-mediated mAChR stimulation led to inhibition of Ca2+ currents through voltage-dependent (VD) and voltage-independent (VI) pathways. Pre-exposure of SG neurons to the M1 receptor blocker, M1-toxin, resulted in VD inhibition of Ca2+ currents after Oxo-M application. On the other hand, VI modulation of Ca2+ currents was observed after pretreatment of cells with methoctramine (M2 mAChR blocker). The Oxo-M-mediated inhibition was nearly eliminated in the presence of both M1 and M2 mAChR blockers but was unaltered when SG neurons were exposed to the M4 mAChR toxin, M4-toxin. Finally, the results from single-cell RT-PCR and immunofluorescence assays indicated that M1 and M2 receptors are expressed and located on the surface of SG neurons. Overall, the results indicate that SG neurons that innervate cardiac muscle express M1 and M2 mAChR, and activation of these receptors leads to inhibition of Ca2+ channel currents through VI and VD pathways, respectively.
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