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.
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