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.

Acetylcholine Deficiency in Caenorhabditis elegans Induced by Hyperthermia Can Be Compensated by ACh-esterase Inhibition or Activation of GAR-3 mAChRs

“…3;Liu et al, 2007;Park, Kim et al, 2003;Steger & Avery, 2004). All of them show high similarity in amino acid sequences to the known mammalian mAChRs M 1 , M 2 , M 3 , M 4 and M 5 , which are coupled to different G-proteins (Caulfield & Birdsall, 1998;Langmead et al, 2008;Lanzafame et al, 2003).…”

“…Muscarinic acetylcholine receptors are known to regulate numerous fundamental physiological processes including muscarinic actions of acetylcholine on peripheral effector tissues and a multitude of central sensory, vegetative and motor functions (Ellis et al, 2006;Erskine et al, 2004;Feiro & Gould, 2005;Lanzafame et al, 2003). Many studies have shown that central muscarinic receptors play an important role in the regulation of body temperature in mammals (Gomeza et al, 1999) and therefore are necessary for survival of these animals and humans at hot environment.…”

“…All of them show high similarity in amino acids sequences to the known mammalian mAChRs M 1 , M 2 , M 3 , M 4 and M 5 , which are coupled to different G-proteins (Caulfield & Birdsall, 1998;Langmead et al, 2008;Lanzafame et al, 2003). To identify mAChRs responsible for the rise in behavior thermotolerance we analyzed available deletions mutants of all of three genes of these receptors by estimation of thermotolerance sensitivity to agonist of mAChRs pilocarpine and inhibitor of ACh-esterase neostigmine.…”

“…However it is possible that role of separate types of synaptic transmission in the whole nervous system dysfunction produced by heat stress can be different. Cholinergic synaptic transmission plays extremely important role in the large majority of functions of human and animals' organisms including thermoregulation (Conti-Tronconi & Raffery, 1982;Ellis et al, 2006;Erskine et al, 2004;Feiro & Gould, 2005;Gomeza et al, 1999;Lanzafame, Christopoulos, & Mitchelson, 2003). Therefore it is possible that cholinergic system plays important role in the response of whole nervous system to hyperthermia including its dysfunctions and compensatory responses.…”

The Non-Neuronal Cholinergic System in Health and Disease

“…M2 and M4 mAChR couple preferentially to G i/9 affecting the adenylyl cyclase activity and inhibiting non-selective cation channels, transient receptor potential channels and potassium channels [20,21]. M1, M3 and M5 mAChR couple to G q/11 and increase intracellular calcium via generation of inositol 1,4,5-trisphosphate and 1,2-diacylglyerol [20,21]. The degradation of ACh into choline and acetate is catalyzed by the enzymes acetylcholinesterase (AChE) and the less specific butyrylcholinesterase.…”