The role of calcium in M-current inhibition by muscarinic agonists in rat sympathetic neurons.
I have investigated the role of Ca2+ on M-current (IK(M)) inhibition by the muscarinic agonist oxo-M using the perforated patch voltage clamp technique. Oxo-M inhibited IK(M) in cultured SCG cells with an IC50 of 1.2 microM in 2 mM [Ca2+]o, and 13.1 microM in nominally Ca(2+)-free external solution. BAPTA-AM, ryanodine and thapsigargin (substances which modulate [Ca2+]i) did not affect IK(M) or the inhibitory action of oxo-M in either 2 or 0 mM extracellular Ca2+. Caffeine (10 mM) inhibited M current by approximately 30% in both 2 and 0 mM [Ca2+]o; this inhibition was not affected by [Ca2+]i modulators. Unexpectedly, the effect of oxo-M (10 microM) was enhanced after application of caffeine (10 mM) in either 2 or 0 mM [Ca2+]o. Thus, the effect of muscarinic agonists on IK(M) was blunted in Ca(2+)-free extracellular solutions, but neither oxo-M nor caffeine appeared to inhibit IK(M) through an elevation of [Ca2+]i. I suggest that resting levels of [Ca2+]i are necessary for a normal inhibition, with lower levels inducing an impairment of the inhibition of IK(M) by muscarinic agonists.
Lamas
J A
JA
Department of Pharmacology, University College London, UK.
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D012433:Ryanodine / Q000494:pharmacology; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D012433:Ryanodine; D002110:Caffeine; D004533:Egtazic Acid; D010095:Oxotremorine; D019284:Thapsigargin; D008274:Magnesium; D002118:Calcium