Abstract
Nicotinic acetylcholine receptor (nAChR) gene expression is regulated by both muscle activity and increased intracellular calcium. This regulation is an important developmental event that rids receptors from the extrajunctional region of the developing muscle fiber. In avian muscle, it has been proposed that muscle activity suppresses nAChR gene expression via calcium-activated protein kinase C (PKC)-dependent phosphorylation of the myogenic transcription factor, myogenin. Here, we examined the role that PKC and other kinases play in mediating calcium- and activity-dependent suppression of nAChR genes in rat primary myotubes. We found that although activated PKC could regulate nAChR promoter activity and transiently suppressed both nAChR and myogenin gene expression, it did not appear to be required for calcium- or activity-dependent control of nAChR gene expression in mammalian muscle. Neither depletion of PKC from myotubes nor specific pharmacological inhibition of PKC blocked the suppression of nAChR gene expression produced by calcium or muscle depolarization. In contrast, we provide evidence that calcium/calmodulin-activated protein kinase II participates in mediating the effects of muscle depolarization on nAChR and myogenin gene expression.
Highlights
Nicotinic acetylcholine receptor gene expression is regulated by both muscle activity and increased intracellular calcium
We had previously documented that increasing intracellular calcium can suppress Nicotinic acetylcholine receptor (nAChR) gene expression in rat muscle [3, 10], we did not know how rapidly this response occurred or whether myogenin was regulated in a similar fashion
Our current understanding of the mechanism by which nAChR gene expression is regulated by muscle activity comes largely from studies of avian muscle
Summary
Nicotinic acetylcholine receptor (nAChR) gene expression is regulated by both muscle activity and increased intracellular calcium. When skeletal muscle is made inactive by denervation or pharmacological treatment with drugs such as the sodium channel blocker tetrodotoxin (TTX), calcium concentrations remain low [4], and extrajunctional expression of the nAChR genes is increased dramatically [5, 6]. Experiments performed in avian muscle have implicated protein kinase C (PKC) as the primary mediator of activity-dependent, calcium-induced suppression of nAChR gene expression [2, 7, 11]. Activated PKC is proposed to phosphorylate myogenin [12, 13], a basic helix-loop-helix myogenic transcription factor that mediates high level nAChR gene expression in inactive muscle (14 –18). This phosphorylation abrogates myogenin binding to target E-box sequences that regulate nAChR promoter activity [12, 13], resulting in reduced nAChR gene expression
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