Cellular Signaling Mechanisms for Muscarinic Acetylcholine Receptors

Abstract

Signaling pathways for muscarinic acetylcholine receptors (mAChRs) include several enzymes and ion channels. Recent studies have revealed the importance of various isoforms of both alpha and betagamma 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 alpha and beta subunits of G(i/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 A(2), 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 M(2) and M(4) mAChR stimulation, although in the rat superior cervical ganglion topographical constraints appear to limit the effect to the M(2) mAChR. Another ganglionic K(+) current, the M current, is inhibited by M(1) mAChR activation, but in murine hippocampus inhibition involves another receptor subtype. R-type Ca(2+) channels are both facilitated and inhibited by M(1) and M(2) mAChRs; facilitation being more pronounced with activation of M(1) mAChRs and inhibition with M(2) mAChRs.

Selective activation of the M 1 muscarinic acetylcholine receptor achieved by allosteric potentiation

“…Among the mAChRs, M 1 is most abundantly expressed in the hippocampus, cortex, and striatum, and localizes to postsynaptic membranes (3), where it signals via G q /G 11 G-proteins to phospholipase C and through other G-proteins to additional signaling systems (4,5). M 1 regulates several ion channels including KCNQ inwardly rectifying K ϩ currents, voltage-gated calcium channels, and NMDA receptors (4)(5)(6)(7)(8)(9).…”

PIP2-Mediated HCN3 Channel Gating Is Crucial for Rhythmic Burst Firing in Thalamic Intergeniculate Leaflet Neurons

“…Recombinant HCN channel function can be modulated by activation of mAChRs (Pian et al, 2007). Thus, PIP 2 -gated HCN3 channels in the IGL may represent an important target for drugs acting at the mAChR signaling pathway (Lanzafame et al, 2003).…”

Chronic ingestion of bisphenol A decreases the cholinergically evoked and spontaneous contractions of rat uterus in vitro

“…[12] Myometrium is innervated by cholinergic parasympathetic fibers and acetylcholine activates the M 2 receptors to bring about the contractions. [13] It has been shown that uterotonic activity of Ficus asperifolia extracts increased uterine contractility involving cholinergic (muscarinic) mechanism. [14] Our observations indicate that BPA exposure decreased.…”