Muscarinic Inhibition of Calcium Current and M Current in Gaq- Deficient Mice

Activation of M1 muscarinic acetylcholine receptors (M1 mAChR) inhibits M-type potassium currents (IK(M) ) and N-type calcium currents (ICa) 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 Gaq (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 Gaq gene. PTX-insensitive M1 mAChR inhibition of ICa was strongly reduced in Gaq 2/2 mouse SCG neurons and was fully restored by acute overexpression of Gaq. In contrast, M1 mAChR inhibition of IK(M) persisted in Gaq2/2 mouse SCG cells. However, unlike rat SCG neurons, muscarinic inhibition of IK(M) was partly PTX-sensitive. Residual (PTX-insensitive) IK(M) inhibition was slightly reduced in Gaq 2/2 neurons, and the remaining response was then suppressed by anti-Gaq/11 antibodies. Bradykinin (BK) also inhibits IK(M) in rat SCG neurons via a PTX-insensitive G-protein (Gq and/or G11; Jones et al., 1995). In mouse SCG neurons, IK(M) inhibition by BK was fully PTXresistant. It was unchanged in Gaq 2/2 mice but was abolished by anti-Gaq/11 antibody. We conclude that, in mouse SCG neurons (1) M1 mAChR inhibition of ICa is mediated principally by Gq, (2) M1 mAChR inhibition of IK(M) is mediated partly by Gq, more substantially by G11, and partly by a PTX-sensitive G-protein(s), and (3) BK-induced inhibition of IK(M) is mediated wholly by G11.