Two distinct pathways of muscarinic current responses in rabbit sino-atrial node myocytes.
Acetycholine (ACh) slows the heart rate by acting on sino-atrial node currents. Low ACh concentrations act on muscarinic receptors to inhibit the hyperpolarization-activated current (if) by a adenosine 3',5'-cyclic monophosphate (cAMP)-dependent cytoplasmic pathway. ACh also activates a muscarinic potassium conductance (iK,ACh) via a pertussis toxin-sensitive guanine nucleotide-binding protein (G-protein) that gates the channel directly. This pathway has been called membrane-delimited or "fast" because cytoplasmic components are not required and hence activation is relatively rapid. Such a pathway has also been proposed for the muscarinic inhibition of if. Here we show that, under steady-state current conditions, 0.1-1 microM ACh activates iK,ACh with a time constant of 1 s or less that is inversely proportional to ACh concentration, consistent with a fast, membrane-delimited pathway. ACh also causes a significantly slower inhibition of if which is not proportional to ACh binding. The changes in if are consistent with muscarinic effects mediated exclusively through the cAMP pathway.
Accili
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Università di Milano, Dipartimento di Fisiologia e Biochimica Generali, Elettrofisiologia, via Celoria 26, I-20133 Milan, Italy. eaaccili@sfu.ca
Redaelli
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DiFrancesco
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D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D019204:GTP-Binding Proteins / Q000502:physiology; D015640:Ion Channel Gating; D007700:Kinetics; D037342:Pertussis Toxin; D011188:Potassium / Q000378:metabolism; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D011976:Receptors, Muscarinic; D010566:Virulence Factors, Bordetella; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000109:Acetylcholine; D011188:Potassium