MUSCARINIC ACETYLCHOLINE-RECEPTORS - SIGNAL-TRANSDUCTION THROUGH MULTIPLE EFFECTORS

Muscarinic receptors regulate a number of important basic physiologic functions including heart rate and motor and sensory control as well a s more complex behaviors including arousal, memory, and learning, Loss of muscarinic receptor number or function has been implicated in the etiology of several neurological disorders including Alzheimer's demen tia, Down's syndrone, and Parkinson's disease. Muscarinic receptors tr ansduce their signals by coupling with G-proteins, which then modulate the activity of a number of effector enzymes and ion channels, Five s ubtypes of muscarinic receptors (m1-m5) have been identified by molecu lar cloning and much has been learned about their distribution, pharma cology, and structure, Less is known about the molecular mechanisms of receptor-effector coupling and the biological role of each receptor s ubtype, The ectopic expression of genes encoding a single muscarinic r eceptor subtype in mammalian cell lines has provided an important mode l system in which to investigate receptor subtype-specific pharmacolog y and signal transduction. Expression models have revealed that single muscarinic receptor m1, m3, or m5 subtypes can activate multiple sign aling effecters simultaneously including phospholipases A2, C, and D, as well as tyrosine kinase and a novel class of voltage-insensitive ca lcium channels, The m2 or m4 receptors have been shown to augment phos pholipase A2 in addition to their established role as inhibitory recep tors acting through the attenuation of adenylate cyclase, In addition to allowing investigations of the regulatory mechanisms of muscarinic receptors, expression models provide an excellent tool to investigate receptor-subtype specific physiology and pharmacology.