Identification of subtypes of muscarinic receptors that regulate Ca2+ and K+ channel activity in sympathetic neurons

Many different G protein-coupled receptors modulate the activity of Ca2+ and K+ channels in a variety of neuronal types. There art: five known subtypes (M-1-M-5) Of muscarinic acetylcholine receptors. Knockout mice lacking the M-1, M-2, or M-4 subtypes are studied to determine which receptors mediate modulation of voltage-gated Ca2+ channels in mouse sympathetic neurons. In these cells, muscarinic agonists modulate N- and L-type Ca2+ channels and the M-type K+ channel through two distinct, G-protein mediated pathways. The fast and voltage-dependent pathway is lacking in the M-2 receptor knockout mice. The slow acid voltage-independent pathway is absent in the M-1 receptor knockout mice. Neither pathway is affected in the M-4 receptor knockout mice. Muscarinic modulation of the M current is absent in the M-1 receptor knockout mice, and can be reconstituted in a heterologous expression system using cloned channels and M-1 receptors. Our results using knockout mice are compared with pharmacological data in the rat. (C) 2001 Elsevier Science Inc. All rights reserved.