Muscarinic inhibition of calcium current and M current in Galpha 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 mammalian sympathetic ganglia. Previous antisense experiments suggested that, in rat superior cervical ganglion (SCG) neurons, both effects were partly mediated by the G-protein Galpha(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 Galpha(q) gene. PTX-insensitive M(1) mAChR inhibition of I(Ca) was strongly reduced in Galpha(q) -/- mouse SCG neurons and was fully restored by acute overexpression of Galpha(q). In contrast, M(1) mAChR inhibition of I(K(M)) persisted in Galpha(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 Galpha(q) -/- neurons, and the remaining response was then suppressed by anti-Galpha(q/11) antibodies. Bradykinin (BK) also inhibits I(K(M)) in rat SCG neurons via a PTX-insensitive 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 Galpha(q) -/- mice but was abolished by anti-Galpha(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 mediated partly by G(q), more substantially by G(11), and partly by a PTX-sensitive G-protein(s), and (3) BK-induced inhibition of I(K(M)) is mediated wholly by G(11).
Haley
J E
JE
Wellcome Laboratory for Molecular Pharmacology, Department of Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
Delmas
P
P
Offermanns
S
S
Abogadie
F C
FC
Simon
M I
MI
Buckley
N J
NJ
Brown
D A
DA
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D037342:Pertussis Toxin; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics; D043782:Receptor, Bradykinin B2; D043643:Receptor, Muscarinic M1; D018002:Receptors, Bradykinin / Q000187:drug effects / Q000235:genetics; D011976:Receptors, Muscarinic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D018721:Muscarinic Agonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D043782:Receptor, Bradykinin B2; D043643:Receptor, Muscarinic M1; D018002:Receptors, Bradykinin; D011976:Receptors, Muscarinic; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D001920:Bradykinin