G‐proteins and G‐protein subunits mediating cholinergic inhibition of N‐type calcium currents in sympathetic neurons

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Abstract
One postsynaptic action of the transmitter acetylcholine in sympathetic ganglia is to inhibit somatic N‐type Ca2+currents: this reduces Ca2+‐activated K+currents and facilitates high‐frequency spiking. Previous experiments on rat superior cervical ganglion neurons have revealed two distinct pathways for this inhibitory action: a rapid, voltage‐dependent inhibition through activation of M4muscarinic acetylcholine receptors (mAChRs), and a slower, voltage‐independent inhibition via M1mAChRs (Hille (1994)Trends in Neurosci.,17,531–536]. We have analysed the mechanistic basis for this divergence at the level of the individual G‐proteins and their α and βγ subunits, using a combination of site‐directed antibody injection, plasmid‐driven antisense RNA expression, over‐expression of selected constitutively active subunits, and antagonism of endogenously liberated βγ subunits by over‐expression of βγ‐binding β‐adrenergic receptor kinase 1 (βARK1) peptide. The results indicate that: (i) M4mAChR‐induced inhibition is mediated by GoA;(ii) α and βγ subunits released from the activated GoAheterotrimer produce separate voltage‐insensitive and voltage‐sensitive components of inhibition, respectively; and (iii) voltage‐insensitive M1mAChR‐induced inhibition is likely to be mediated by the α subunit of Gq. Hence, Ca2+current inhibition results from the concerted, but independent actions of three different G‐protein subunits.

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