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CaM kinase II-dependent suppression of nicotinic acetylcholine receptor delta-subunit promoter activity

H Tang1, Z Sun, D Goldman

  • 1Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.

The Journal of Biological Chemistry
|May 15, 2001
PubMed

Insights

Muscle activity and calcium suppress nicotinic acetylcholine receptor (nAChR) gene expression. Calcium/calmodulin-dependent protein kinase II (CaM kinase II) mediates this suppression in mammalian muscle by inhibiting myogenin binding to the nAChR promoter.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Muscle Physiology

Background:

  • Muscle activity, triggered by nerve impulses, reduces nicotinic acetylcholine receptor (nAChR) gene expression.
  • This suppression is linked to increased intracellular calcium levels and mediated by E-box sequences in the nAChR promoter, which bind myogenic helix-loop-helix transcription factors.
  • While protein kinase C (PKC) mediates this in chick muscle, its role in mammalian skeletal muscle is unclear.

Purpose of the Study:

  • To identify calcium-regulated enzymatic activities that mediate the effects of muscle activity and calcium on nAChR promoter activity in mammalian skeletal muscle.
  • To investigate the role of calcium/calmodulin-dependent protein kinase II (CaM kinase II) in regulating nAChR gene expression.

Main Methods:

  • Utilized rat primary muscle cultures to screen for calcium-regulated enzymatic activities.
  • Investigated the effect of CaM kinase II on nAChR promoter activity using specific promoter sequences.
  • Performed in vitro protein/DNA interaction studies to analyze the binding of myogenic factors to the nAChR promoter.

Main Results:

  • Calcium/calmodulin-dependent protein kinase II (CaM kinase II) was found to specifically suppress nAChR promoter activity in mammalian muscle.
  • This suppression was mediated by an E-box sequence within the nAChR delta-subunit gene's activity-dependent enhancer.
  • CaM kinase II was shown to inhibit the binding of myogenin to this promoter region.
  • CaM kinase activity increases in active muscle, and its inhibition leads to increased nAChR delta-promoter activity.

Conclusions:

  • CaM kinase II plays a significant role in suppressing nAChR gene expression in response to muscle activity and increased intracellular calcium in mammalian muscle.
  • CaM kinase II may be a key mediator linking muscle depolarization to changes in nAChR gene expression.
  • This finding highlights a previously unappreciated mechanism in the regulation of neuromuscular junctions.

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