α2δ1 dihydropyridine receptor subunit is a critical element for excitation-coupled calcium entry but not for formation of tetrads in skeletal myotubes

Marcin P. Gach, Gennady Cherednichenko, Claudia Haarmann, Jose R. Lopez, Kurt G. Beam, Isaac N Pessah, Clara Franzini-Armstrong, Paul D. Allen

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Abstract

It has been shown that small interfering RNA (siRNA) partial knockdown of the α2δ1 dihydropyridine receptor subunits cause a significant increase in the rate of activation of the L-type Ca 2+ current in myotubes but have little or no effect on skeletal excitation-contraction coupling. This study used permanent siRNA knockdown of α2δ1 to address two important unaddressed questions. First, does the α2δ1 subunit contribute to the size and/or spacing of tetradic particles? Second, is the α2δ1 subunit important for excitation-coupled calcium entry? We found that the size and spacing of tetradic particles is unaffected by siRNA knockdown of α2δ1, indicating that the visible particle represents the α1s subunit. Strikingly, >97% knockdown of α2δ1 leads to a complete loss of excitation-coupled calcium entry during KCl depolarization and a more rapid decay of Ca2+ transients during bouts of repetitive electrical stimulation like those occurring during normal muscle activation in vivo. Thus, we conclude that the α2δ 1 dihydropyridine receptor subunit is physiologically necessary for sustaining Ca2+ transients in response to prolonged depolarization or repeated trains of action potentials.

Original languageEnglish (US)
Pages (from-to)3023-3034
Number of pages12
JournalBiophysical Journal
Volume94
Issue number8
DOIs
StatePublished - Apr 15 2008

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ASJC Scopus subject areas

  • Biophysics

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