Muscarinic inhibition of calcium current and M current in G alpha(q)-deficient mice

Activation of M-1 muscarinic acetylcholine receptors (M-1 mAChR) inhibits M -type potassium currents (I-K(M)) and N-type calcium currents (I-Ca) in mam malian sympathetic ganglia. Previous antisense experiments suggested that, in rat superior cervical ganglion (SCG) neurons, both effects were partly m ediated by the G-protein G alpha(q) (Delmas et al., 1998a; Haley et al., 19 98a), but did not eliminate a contribution by other pertussis toxin (PTX)-i nsensitive G-proteins. We have tested this further using mice deficient in the G alpha(q) gene. PTX-insensitive M-1 mAChR inhibition of I-Ca was strongly reduced in G alph a(q) -/- mouse SCG neurons and was fully restored by acute overexpression o f G alpha(q). In contrast, M-1 mAChR inhibition of I-K(M) persisted in G al pha(q) -/- mouse SCG cells. However, unlike rat SCG neurons, muscarinic inh ibition of I-K(M) was partly PTX-sensitive. Residual (PTX-insensitive) I-K( M) inhibition was slightly reduced in G alpha(q) -/- neurons, and the remai ning response was then suppressed by anti-G alpha(q/11) antibodies. Bradykinin (BK) also inhibits I-K(M) in rat SCG neurons via a PTX-insensiti ve G-protein (G(q) and/or G(11); Jones et al., 1995). In mouse SCG neurons, I-K(M) inhibition by BK was fully PTX-resistant. It was unchanged in G alp ha(q) -/- mice but was abolished by anti-G alpha(q/11) antibody. We conclude that, in mouse SCG neurons (1) M-1 mAChR inhibition of I-Ca is mediated principally by G(q), (2) M-1 mAChR inhibition of I-K(M) is mediate d partly by G(q), more substantially by G(11), and partly by a PTX-sensitiv e G-protein(s), and (3) BK-induced inhibition of I-K(M) is mediated wholly by G(11).