Muscarinic agonist potencies at three different effector systems linked to the M_2 or M_3 receptor in longitudinal smooth muscle of guinea-pig small intestine

摘要

1 The abilities of muscarinic agonists (arecoline, bethanechol, carbachol, McN-A343, methacho-line, pilocarpine) to inhibit isoprenaline-induced cyclic AMP production in chopped fragments (via M_2 receptors), and to evoke cationic current (I_(cat)) (via M_2 receptors) or calcium store release (via M3 receptors) in enzyme-dispersed, single voltage-clamped cells from longitudinal smooth muscle of the guinea-pig small intestine were examined. 2 All muscarinic agonists (1-300 μM) examined inhibited isoprenaline (1 μM)-induced accumulation of cyclic AMP, the IC_(50) varying from 52 to 248 μM. However, their relative potencies to evoke this M_2 effect were not significantly correlated with their ability to evoke I_(cat), also a M_2 effect, whether or not calcium stores were depleted; pilocarpine and McN-A343 inhibited the I_(cat) response to carbachol. 3 Muscarinic agonists (concentration 300 or 1000 μM), except pilocarpine and McN-A343 which were ineffective, evoked Ca~(2+)-activated K~+ current (I_(K-CA)) resulting from Ca~(2+) store release (M_3 effect). Their effectiveness was tested by estimating residual stored calcium by subsequent application of caffeine (10 mM). The relative potencies to evoke Ca~(2+) store release (M_3) and for I_(cat) activation (M_2) were closely correlated (P<0.001). 4 These data might be explained if M_2-mediated adenylyl cyclase inhibition and I_(cat) activation involve different G proteins, or involve different populations of M_2 receptors. The observed correlation of agonist potency between I_(cat) activation and Ca~(2+) store release supports the proposal (Zholos & Bolton, 1997) that M_3 activation can potentiate M_2-cationic channel coupling through Ca~(2+)-independent mechanisms.