Luminal Ca <sup>2+</sup> Controls Termination and Refractory Behavior of Ca <sup>2+</sup> -Induced Ca <sup>2+</sup> Release in Cardiac Myocytes

Circulation Research - Tập 91 Số 5 - Trang 414-420 - 2002
Dmitry Terentyev1,2, Serge Viatchenko‐Karpinski1,2, Héctor H. Valdivia1, Ariel L. Escobar1,2, Sándor Györke1
1From Texas Tech University HSC (D.T., S.V.-K., A.L.E., S.G.), Lubbock, Tex; and the University of Wisconsin (H.H.V.), Madison, Wis.
2the University of Wisconsin (H.H.V.), Madison, Wis.

Tóm tắt

Despite extensive research, the mechanisms responsible for the graded nature and early termination of Ca 2+ -induced Ca 2+ release (CICR) from the sarcoplasmic reticulum (SR) in cardiac muscle remain poorly understood. Suggested mechanisms include cytosolic Ca 2+ -dependent inactivation/adaptation and luminal Ca 2+ -dependent deactivtion of the SR Ca 2+ release channels/ryanodine receptors (RyRs). To explore the importance of cytosolic versus luminal Ca 2+ regulatory mechanisms in controlling CICR, we assessed the impact of intra-SR Ca 2+ buffering on global and local Ca 2+ release properties of patch-clamped or permeabilized rat ventricular myocytes. Exogenous, low-affinity Ca 2+ buffers (5 to 20 mmol/L ADA, citrate or maleate) were introduced into the SR by exposing the cells to “internal” solutions containing the buffers. Enhanced Ca 2+ buffering in the SR was confirmed by an increase in the total SR Ca 2+ content, as revealed by application of caffeine. At the whole-cell level, intra-SR [Ca 2+ ] buffering dramatically increased the magnitude of Ca 2+ transients induced by I Ca and deranged the smoothly graded I Ca -SR Ca 2+ release relationship. The amplitude and time-to-peak of local Ca 2+ release events, Ca 2+ sparks, as well as the duration of local Ca 2+ release fluxes underlying sparks were increased up to 2- to 3-fold. The exogenous Ca 2+ buffers in the SR also reduced the frequency of repetitive activity observed at individual release sites in the presence of the RyR activator Imperatoxin A. We conclude that regulation of RyR openings by local intra-SR [Ca 2+ ] is responsible for termination of CICR and for the subsequent restitution behavior of Ca 2+ release sites in cardiac muscle.

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Circulation Research

Tập 91 Số 5

414-420

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