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 are five known subtypes (M1-M5) of muscarinic acetylcholine receptors. Knockout mice lacking the M1, M2, or M4 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 M2 receptor knockout mice. The slow and voltage-independent pathway is absent in the M1 receptor knockout mice. Neither pathway is affected in the M4 receptor knockout mice. Muscarinic modulation of the M current is absent in the M1 receptor knockout mice, and can be reconstituted in a heterologous expression system using cloned channels and M1 receptors. Our results using knockout mice are compared with pharmacological data in the rat.
Shapiro
M S
MS
Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle 98195-7290, USA. shapirom@uthscsa.edu
Gomeza
J
J
Hamilton
S E
SE
Hille
B
B
Loose
M D
MD
Nathanson
N M
NM
Roche
J P
JP
Wess
J
J
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010095:Oxotremorine / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D017783:Superior Cervical Ganglion / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D015220:Calcium Channels; D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D015221:Potassium Channels; D020033:Protein Isoforms; D011976:Receptors, Muscarinic; D010095:Oxotremorine; D019204:GTP-Binding Proteins; D005033:Ethylmaleimide