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

Abstract

Activation of M1 muscarinic acetylcholine receptors (M1 mAChR) inhibits M-type potassium currents (I(K(M))) and N-type calcium currents (I(Ca)) in mammalian sympathetic ganglia. Previous antisense experiments suggested that, in rat superior cervical ganglion (SCG) neurons, both effects were partly mediated by the G-protein Gα(q) (Delmas et al., 1998a; Haley et al., 1998a), but did not eliminate a contribution by other pertussis toxin (PTX)-insensitive G-proteins. We have tested this further using mice deficient in the Gα(q) gene. PTX-insensitive M1 mAChR inhibition of I(Ca) was strongly reduced in Gα(q) -/- mouse SCG neurons and was fully restored by acute overexpression of Gα(q). In contrast, M1 mAChR inhibition of I(K(M)) persisted in Gα(q) -/- mouse SCG cells. However, unlike rat SCG neurons, muscarinic inhibition of I(K(M)) was partly PTX-sensitive. Residual (PTX-insensitive) I(K(M)) inhibition was slightly reduced in Gα(q) -/- neurons, and the remaining response was then suppressed by anti-Gα(q/11) antibodies. Bradykinin (BK) also inhibits I(K(M)) in rat SCG neurons via a PTX-insensitive G-protein (G(q) and/or G11; Jones et al., 1995). In mouse SCG neurons, I(K(M)) inhibition by BK was fully PTX-resistant. It was unchanged in Gα(q) -/- mice but was abolished by anti-Gα(q/11) antibody. We conclude that, in mouse SCG neurons (1) M1 mAChR inhibition of I(Ca) is mediated principally by G(q), (2) M1 mAChR inhibition of I(K(M)) is mediated partly by G(q), more substantially by G11, and partly by a PTX-sensitive G- protein(s), and (3) BK-induced inhibition of I(K(M)) is mediated wholly by G11.