SUBTYPES OF THE MUSCARINIC RECEPTOR IN SMOOTH-MUSCLE

Muscarinic receptors are expressed in smooth muscle throughout the bod y. In most instances, the muscarinic receptor population in smooth mus cle is composed of mainly the M-2 and M-3 subtypes in an 80% to 20% mi xture. The M-3 subtype mediates phosphoinositide hydrolysis and calciu m mobilization, whereas the M-2 subtype mediates an inhibition of cAMP accumulation. In addition, a variety of ionic conductances are elicit ed by muscarinic receptors. Muscarinic agonists stimulate a nonselecti ve cation conductance that is pertussis toxin-sensitive and dependent on calcium. The pertussis toxin-sensitivity of this response suggests that it is mediated by M-2 receptors. Following agonist induced depola rization of smooth muscle, voltage dependent calcium channels are acti vated to enable an influx of calcium. In some instances, muscarinic ag onists enhance this conductance through a mechanism involving protein kinase C, whereas in other instances, muscarinic agonists suppress thi s calcium conductance. Smooth muscle often contains calcium activated potassium channels that tend to repolarize the membrane following calc ium influx. Activation of muscarinic receptors suppresses this potassi um conductance in some smooth muscles. Under standard conditions, musc arinic agonists elicit pertussis toxin-insensitive contractions throug h activation of the M-3 receptor. When most of the M-3 receptors are i nactivated, it is possible to measure a pertussis toxin-sensitive cont ractile response to muscarinic agonists that is most likely mediated t hrough M-2 receptors. M-2 receptors also cause an indirect contraction by inhibiting the relaxant effects of agents that increase cAMP (e.g. , forskolin and isoproterenol).