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

Jane E. Haley¹, Patrick Delmas¹, Stefan Offermanns², Fe C. Abogadie¹, Melvin I. Simon², Noel J. Buckley¹, and David A. Brown¹

¹ Wellcome Laboratory for Molecular Pharmacology, Department of Pharmacology, University College London, London, WC1E 6BT, United Kingdom, and ² Division of Biology, California Institute of Technology, Pasadena, California 91125

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 G_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 G_q gene.

PTX-insensitive M₁ mAChR inhibition of I_Ca was strongly reduced in G_q / mouse SCG neurons and was fully restored by acute overexpression of G_q. In contrast, M₁ mAChR inhibition of I_K(M) persisted in G_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 G_q / neurons, and the remaining response was then suppressed by anti-G_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 G_q / mice but was abolished by anti-G_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.

Key words: M current; calcium current; G-protein; superior cervical ganglion neuron; knock-out mouse; muscarinic receptor; bradykinin receptor

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20113973-07$05.00/0

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