ELECTRICAL-ACTIVITY SUPPRESSES NICOTINIC ACETYLCHOLINE-RECEPTOR GAMMA-SUBUNIT PROMOTER ACTIVITY

Nicotinic acetylcholine receptors are pentameric, transmembrane, ligan d-gated ion channels critical for neuromuscular signal transmission. P rior to innervation, the genes encoding these receptors are expressed in nuclei throughout the muscle fiber. Muscle innervation leads to a d ramatic decrease in expression of these genes in extrasynaptic nuclei. This reduction in gene expression can be reversed by muscle denervati on. The effects of denervation on receptor gene expression can be bloc ked by electrical stimulation of muscle using extracellular electrodes . The molecular mechanisms by which muscle electrical activity leads t o altered patterns of nicotinic acetylcholine receptor gene expression are not well understood. rising an in vitro electrical stimulation pa radigm to induce muscle activity, we have been able to mimic the effec t of innervation on extrasynaptic acetylcholine receptor gene expressi on. We have found that a 93-bp region of 5'-flanking DNA, spanning nuc leotides -150 to -57 relative to the transcription start site of the g amma subunit gene, is required for the suppression of gene expression in response to muscle activity. Sequences downstream of this region ar e transcriptionally active but are not responsive to muscle activity. However, these downstream sequences become responsive to muscle activi ty when placed under the control of the gamma subunit muscle-specific enhancer. (C) 1995 Academic Press, Inc.