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Mouse muscle denervation increases expression of an 7 nicotinic receptor with unusual pharmacology

Hiroshi Tsuneki, Ramiro Salas and John A. Dani

Neuronal nicotinic 7 subunits have been found in chick and rat skeletal muscle during development and denervation. In the present study, reverse transcriptase-polymerase chain reaction was used to detect 7 subunit mRNA in denervated mouse muscle. To determine whether the 7 subunit forms functional nicotinic acetylcholine receptors (nAChRs) in muscle, choline was used to induce a membrane depolarization because choline has been considered a specific agonist of 7-containing (7*) nAChRs. We found, however, that choline (3-10 mM) also weakly activates muscle nAChRs. After inhibiting muscle nAChRs with a specific muscle nAChR inhibitor, -conotoxin GI (CTxGI), choline was used to activate the 7* nAChRs on muscle selectively. Four weeks after denervation, rapid application of choline (10 mM) elicited a substantial depolarization in the presence of CTxGI (0.1 µM). This component of the depolarization was never present in denervated muscles obtained from mutant mice lacking the 7 subunit (i.e. 7-null mice). The depolarization component that is resistant to CTxGI was antagonized by pancuronium (3-10 µM) and by a 4-oxystilbene derivative (F3, 0.1-0.5 µM) at concentrations considered highly specific for 7* nAChRs. Another selective 7 antagonist, methyllycaconitine (0.05-5 µM), did not strongly inhibit this choline-induced depolarization. Furthermore, the choline-sensitive nAChRs showed little desensitization over 10 s of application with choline (10-30 mM). These results indicate that functional 7* nAChRs are significantly present on denervated muscle, and that these receptors display unusual functional and pharmacological characteristics.

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