There are five known subtypes of muscarinic receptors (M1-M5). We have used knockout mice lacking the M1, M2, or M4 receptors to determine which subtypes mediate modulation of voltage-gated Ca2+ channels in mouse sympathetic neurons. Muscarinic agonists modulate N- and L-type Ca2+ channels in these neurons through two distinct G-protein-mediated mechanisms. One pathway is fast and membrane-delimited and inhibits N- and P/Q-type channels by shifting their activation to more depolarized potentials. The other is slow and voltage-independent and uses a diffusible cytoplasmic messenger to inhibit both Ca2+ channel types. Using patch-clamp methods on acutely dissociated sympathetic neurons, we isolated each pathway by pharmacological and kinetic means and found that each one is nearly absent in a particular knockout mouse. The fast and voltage-dependent pathway is lacking in the M2 receptor knockout mice; the slow and voltage-independent pathway is absent from the M1 receptor knockout mice; and neither pathway is affected in the M4 receptor knockout mice. The knockout effects are clean and are apparently not accompanied by compensatory changes in other muscarinic receptors.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Sep 14 1999|
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