Modulation of Cardiac Ryanodine Receptor Channels by Alkaline Earth CationsReportar como inadecuado

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Cardiac ryanodine receptor RyR2 function is modulated by Ca2+ and Mg2+. To better characterize Ca2+ and Mg2+ binding sites involved in RyR2 regulation, the effects of cytosolic and luminal earth alkaline divalent cations M2+: Mg2+, Ca2+, Sr2+, Ba2+ were studied on RyR2 from pig ventricle reconstituted in bilayers. RyR2 were activated by M2+ binding to high affinity activating sites at the cytosolic channel surface, specific for Ca2+ or Sr2+. This activation was interfered by Mg2+ and Ba2+ acting at low affinity M2+-unspecific binding sites. When testing the effects of luminal M2+ as current carriers, all M2+ increased maximal RyR2 open probability compared to Cs+, suggesting the existence of low affinity activating M2+-unspecific sites at the luminal surface. Responses to M2+ vary from channel to channel heterogeneity. However, with luminal Ba2+or Mg2+, RyR2 were less sensitive to cytosolic Ca2+ and caffeine-mediated activation, openings were shorter and voltage-dependence was more marked compared to RyR2 with luminal Ca2+or Sr2+. Kinetics of RyR2 with mixtures of luminal Ba2+-Ca2+ and additive action of luminal plus cytosolic Ba2+ or Mg2+ suggest luminal M2+ differentially act on luminal sites rather than accessing cytosolic sites through the pore. This suggests the presence of additional luminal activating Ca2+-Sr2+-specific sites, which stabilize high Po mode less voltage-dependent and increase RyR2 sensitivity to cytosolic Ca2+ activation. In summary, RyR2 luminal and cytosolic surfaces have at least two sets of M2+ binding sites specific for Ca2+ and unspecific for Ca2+-Mg2+ that dynamically modulate channel activity and gating status, depending on SR voltage.

Autor: Paula L. Diaz-Sylvester, Maura Porta, Julio A. Copello



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