Abstract
Nerve-induced muscle activity suppresses nicotinic acetylcholine receptor (nAChR) gene expression by increasing intracellular calcium levels. This suppression is mediated by nAChR promoter sequences harboring at least 1 E-box (CANNTG) that bind myogenic helix-loop-helix transcription factors. How muscle depolarization or increased calcium mediates changes in nAChR promoter activity is not well understood. In chick muscle, protein kinase C (PKC) activation is necessary for activity-dependent nAChR gene suppression. Similar effects of PKC activation have not been found in mammalian skeletal muscle. Therefore, we used rat primary muscle cultures to screen for other calcium-regulated enzymatic activities that may mediate the effects of muscle activity and calcium on nAChR promoter activity. We report here that calcium/calmodulin-dependent protein kinase II (CaM kinase II) can specifically suppress nAChR promoter activity in mammalian muscle. This regulation was mediated by a single E-box sequence residing in the previously characterized nAChR delta-subunit genes 47-base pair activity-dependent enhancer. In vitro protein/DNA interaction studies suggest that CaM kinase II inhibits binding of the myogenic factor, myogenin, to the delta-promoter 47-base pair activity-dependent enhancer. CaM kinase activity is increased in active muscle and inhibition of this enzymatic activity results in increased nAChR delta-promoter activity. Therefore, CaM kinase II may represent a previously unappreciated activity that participates in coupling muscle depolarization to nAChR gene expression.
Highlights
The nicotinic acetylcholine receptor1 is a pentameric integral membrane protein that mediates communication between nerve and muscle
CaM Kinase II-dependent Suppression of ␦-Promoter Activity Is Mediated by the ␦-Promoter 47-bp Activity-dependent Enhancer—We have previously shown that muscle activity and increased intracellular calcium mediate their effects on ␦-promoter activity via a 47-bp enhancer sequence [7, 15]
The main finding from this study is that CaM kinase II can suppress nicotinic acetylcholine receptor (nAChR) ␦-subunit promoter activity by inhibiting binding of a myogenin-containing protein complex to the ␦-promoter 47-bp enhancer
Summary
The nicotinic acetylcholine receptor (nAChR) is a pentameric integral membrane protein that mediates communication between nerve and muscle. Nerve-derived neuregulins mediate their effects via a Ras/mitogen-activated protein kinase signal transduction cascade that activates Ets family transcription factors and bind cis-acting regulatory sequences in the nAChR subunit gene promoters [3,4,5]. NAChR promoter elements necessary for conferring activitydependent regulation have been identified in both birds and mammals [11,12,13,14,15] These elements contain one or more E-boxes (CANNTG), that bind myogenic basic helix-loop-helix transcription factors [12, 13, 16, 17]. It has been proposed that muscle activity suppresses nAChR subunit gene expression by a calcium-dependent activation of PKC that results in phosphorylation of myogenin, abrogating its ability to bind DNA [26]. The mechanism underlying this phenomenon is still not known
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