Relationship between muscarinic receptor reserve and mode of excitation-contraction coupling in airway smooth muscle

Abstract

Acetytcholine-induced contractile response in airway smooth muscle is mediated predominantly via the stimulation of M3 muscarinic receptor subtype The mode of coupling between this stimulation and muscle contraction is pharmacomechanical, i.e. independent of membrane potential by opposition to an electromechanical mode which is membrane potential dependent. We have postulated that muscarinic receptor reserve for contraction induced by agonist controls the mode of excitation-contraction coupling in airway smooth muscle. A fraction of the muscarinic receptor was inactivated with phenoxybenzamine (PBZ), and the relaxing effect of cromakalim (a K+ channel opener) on ACh-induced tonic contraction was determined in those conditions as an index for electromechanical coupling. Quantification of the decrease in receptor density following alkylation of muscarinic receptors by PBZ was confirmed using radioligand binding experiment. The results showed that maximal responses to ACh could still be elicited when functional receptors were reduced to 50 % following the treatment of PBZ (3 μM), indicating the presence of a large receptor reserve for ACh However, the effect of cromakalim was significantly increased following the diminution of muscarinic receptor as compare to the control (p < 0 01, n = 6) Therefore, reduction of muscarinic receptor reserve can switch the excitation-contraction coupling mode from pharmacomechanical to electromechanical coupling.