Orthograde dihydropyridine receptor signal regulates ryanodine receptor passive leak

José Miguel Eltit, Hongli Li, Christopher W. Ward, Tadeusz Molinski, Isaac N Pessah, Paul D. Allen, José R. Lopez

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31 Scopus citations

Abstract

The skeletal muscle dihydropyridine receptor (DHPR) and ryanodine receptor (RyR1) are known to engage a form of conformation coupling essential for muscle contraction in response to depolarization, referred to as excitation-contraction coupling. Here we use WT and CaV1.1 null (dysgenic) myotubes to provide evidence for an unexplored RyR1-DHPR interaction that regulates the transition of the RyR1 between gating and leak states. Using double-barreled Ca2+-selective microelectrodes, we demonstrate that the lack of CaV1.1 expression was associated with an increased myoplasmic resting [Ca2+] ([Ca2+]rest), increased resting sarcolemmal Ca2+ entry, and decreased sarcoplasmic reticulum (SR) Ca2+ loading. Pharmacological control of the RyR1 leak state, using bastadin 5, reverted the three parameters to WT levels. The fact that Ca 2+ sparks are not more frequent in dysgenic than in WT myotubes adds support to the hypothesis that the leak state is a conformation distinct from gating RyR1s. We conclude from these data that this orthograde DHPR-to-RyR1 signal inhibits the transition of gated RyR1s into the leak state. Further, it suggests that the DHPR-uncoupled RyR1 population in WT muscle has a higher propensity to be in the leak conformation. RyR1 leak functions are to keep [Ca2+]rest and the SR Ca2+ content in the physiological range and thus maintain normal intracellular Ca2+ homeostasis.

Original languageEnglish (US)
Pages (from-to)7046-7051
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number17
DOIs
StatePublished - Apr 26 2011

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Keywords

  • L-type calcium channel
  • Resting calcium

ASJC Scopus subject areas

  • General

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