Abstract. Muscle activity alters the expression of functionally distinct nicotinic acetylcholine receptors (nAChR) via regulation of subunit gene expression. Denervation increases the expression of all subunit genes and promotes the expression of embryonic-type (et213~) nAChRs, while electrical stimulation of denervated muscle prevents this induction. We have discovered that the denervation-induced increases in a, 13, % and ~ subunit gene expression do not persist in muscles that have been denervated for periods extending beyond a couple of months. However, expression of RNA encoding the e-subunit remains elevated suggesting a return to expression of predominantly adult-type (OLe~3~e) nAChR in long-term denervated muscles; a finding confirmed by single channel patch-clamp analysis. Since the nAChR subunit genes are regulated by the MyoD family of muscle regulatory factors, and the genes encoding these factors are also induced following short-term muscle denervation, we determined their level of expression in long-term denervated muscle. Although MyoD and myf-5 RNA levels remained elevated, myogenin and MRF4 RNAs were induced only transiently by muscle denervation. Surprisingly, Id-1, a negative regulator of transcription, was gradually induced in denervated muscle with RNA levels peaking about two months after denervation. It is likely that this maintained level of increased Id expression, in conjunction with the returning levels of myogenin and MRF4 expression, account for the reduced level of embryonic receptors in long-term denervated muscle. These changing patterns of gene expression may have important consequences for the ability of muscle to recover function after denervation.T HE muscle nicotinic acetylcholine receptor (nAChR) t is a pentameric integral membrane protein that functions as a ligand-gated ion channel. During muscle development the levels, distribution, and properties of this receptor change (for review see Brehm and Henderson, 1988;Hall and Sanes, 1993). Many of these changes are correlated with muscle innervation. Before innervation, or after denervation of adult muscle embryonictype nAChRs are expressed throughout the muscle fiber. These receptors are composed of four different subunits with a stoichiometry of tx213-,/~. After innervation of muscle, the ",/ subunit is replaced by an ~ subunit, and these adult-type receptors (et2[3e~) are preferentially expressed at the neuromuscular junction (NMJ).The switch from embryonic to adult-type receptors resuits in a change in their channel properties. Embryonic-

Neurally evoked muscle electrical subunit promoter activity. Finally, we show that this activity suppresses nicotinic acetylcholine receptor decreased promoter activity is mediated through the (nAChR) gene expression in extrajunctional domains same DNA sequences that control activity-dependent of adult muscle fibers. It has been proposed that this gene expression. Therefore, we propose that in rat regulation is mediated by calcium influx through voltmuscle, calcium release from the SR participates in age-dependent L-type calcium channels but bypasses coupling muscle depolarization to nAChR gene the sarcoplasmic reticulum in chick and mouse C2C12 expression. ᭧ 1998 John Wiley & Sons, Inc. J Neurobiol 35: 245-cells. Here we report that in rat muscle calcium influx 257, 1998 through L-type calcium channels preferentially re-Keywords: muscle; nicotinic acetylcholine receptor; duced nAChR 1-subunit RNA via a post-transcripactivity-dependent gene expression; calcium; sarcotional mechanism. In contrast, calcium release from plasmic reticulum the sarcoplasmic reticulum (SR) suppressed nAChR

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