Like other neurotransmitter receptors, muscarinic acetylcholine receptors are subject to regulation by the state of receptor activation. Prolonged increases in the concentration of muscarinic agonists result in a decrease in receptor density and loss of receptor sensitivity, both in vivo and in vitro. On the other hand, when the receptor is deprived of acetylcholine for a long duration in vivo, the receptor becomes more sensitive in responding to muscarinic agonists. However, it has been more difficult to demonstrate increases in receptor concentration that accompany this supersensitive state. The purpose of this review is to provide current information related to the characteristics of muscarinic receptor regulation and the molecular mechanisms underlying this phenomenon, regarding both the density of receptors and their transduction mechanisms. Furthermore, possible feedback regulatory roles of different second messenger signals are discussed. Particular emphasis is dedicated to molecular mechanisms of regulation of neuronal muscarinic receptors.
Bibliographical noteFunding Information:
The neurotransmitter acetylcholine interacts with cell surface muscarinic and nicotinic receptors, which differ in location and biological response as well as agonist and antagonist selectivity. In the central nervous system, muscarinic receptors constitute the majority of receptors of the cholinergic type. Activation of muscarinic receptors triggers a variety of intracellular signals, which play important roles in neuronal function. These signals include increased phosphoinositide hydrolysis and cyclic GMP synthesis and a decrease in cyclic AMP levels (for reviews see Refs. 73, 79, and 108). All of these The authors would like to acknowledge the support from NIH (AG-07118 and NS-25743) and the U.S. Army Research Office (DAAL-03-88-0078) during writing this review article. E.E. El-Fakahany is a recipient of a Research Career Development Award from NIH (AG-00344). C.L. Cioffi was supported by a postdoctoral training grant from NIH (MH-15794). Correspondence should be addressed to Esam E. El-Fakahany. Received: March 28, 1990; accepted May 17, 1990.
- Adenylate cyclase
- Cyclic GMP
- Muscarinic receptor
- Phosphoinositide hydrolysis
- Receptor subtypes
- Second messengers