Multiple pertussis toxin‐sensitive G‐proteins can couple receptors to GIRK channels in rat sympathetic neurons when expressed heterologously, but only native Gi‐proteins do soin situ

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Abstract
Although many G‐protein‐coupled neurotransmitter receptors are potentially capable of modulating both voltage‐dependent Ca2+ channels (ICa) and G‐protein‐gated K+ channels (IGIRK), there is a substantial degree of selectivity in the coupling to one or other of these channels in neurons. Thus, in rat superior cervical ganglion (SCG) neurons, M2 muscarinic acetylcholine receptors (mAChRs) selectively activate IGIRK whereas M4 mAChRs selectively inhibit ICa. One source of selectivity might be that the two receptors couple preferentially to different G‐proteins. Using antisense depletion methods, we found that M2 mAChR‐induced activation of IGIRK is mediated by Gi whereas M4 mAChR‐induced inhibition of ICa is mediated by GoA. Experiments with the βγ‐sequestering peptides α‐transducin and βARK1C‐ter indicate that, although both effects are mediated by G‐protein βγ subunits, the endogenous subunits involved in IGIRK inhibition differ from those involved in ICa inhibition. However, this pathway divergence does not result from any fundamental selectivity in receptor–G‐protein–channel coupling because both IGIRK and ICa modulation can be rescued by heterologously expressed Gi or Go proteins after the endogenously coupled α‐subunits have been inactivated with Pertussis toxin (PTX). We suggest instead that the divergence in the pathways activated by the endogenous mAChRs results from a differential topographical arrangement of receptor, G‐protein and ion channel.

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