Cellular Signaling Mechanisms for Muscarinic Acetylcholine Receptors

Signaling pathways for muscarinic acetylcholine receptors (mAChRs) include several enzymes and ion channels. Recent studies have revealed the importance of various isoforms of both α and βγ subunits of G proteins in initiation of signaling as well as the role of the small monomeric G protein, Rho, in the activation of phospholipase D. Modulation of adenylyl cyclase activity by mAChRs appears more diverse as the interaction of various receptor subtypes with the many isoforms of the enzyme are studied. Both α and β subunits of Gi/o may be involved. Some mAChR responses arise through release of nitric oxide from nitrergic nerves, including salivary gland secretion and hippocampal slow wave activity. mAChRs utilize a variety of intracellular pathways to activate various mitogen-activated protein kinases. The kinases are involved in cholinergic regulation of kidney epithelial function, catabolism of amyloid precursor protein, hippocampal long-term potentiation, activation of phospholipase A2, and gene induction. mAChR activation can also stimulate or inhibit cellular growth and apoptosis, dependent on prior levels of cellular activity. Modulation of ion channels by mAChR agonists appears increasingly complex, based on recent studies. K + channels may be activated by M2 and M4 mAChR stimulation, although in the rat superior cervical ganglion topographical constraints appear to limit the effect to the M2 mAChR. Another ganglionic K + current, the M current, is inhibited by M1 mAChR activation, but in murine hippocampus inhibition involves another receptor subtype. R-type Ca 2+ channels are both facilitated and inhibited by M1 and M2 mAChRs; facilitation being more pronounced with activation of M1 mAChRs and inhibition with M2 mAChRs.