Receptor de rianodina, fuga de calcio y arritmias / Ryanodine receptor, calcium leak and arrhythmias

La participación del canal de Ca2+/receptor de rianodina en el acoplamiento excitación-contracción cardiaco se conoce desde finales de los años ochenta, cuando en varios trabajos trascendentales se comunicó por primera vez su purificación y se encontró que correspondía a las estructuras conocidas como «pies¼ localizadas en las cisternas terminales del retículo sarcoplásmico. Adicionalmente a su papel como canal responsable del aumento global y transitorio de Ca2+ que activa a la maquinaria contráctil durante el ciclo cardiaco, el receptor de rianodina también libera Ca2+ durante la fase de relajación, dando lugar a la fuga de Ca2+ en la diástole que en condiciones fisiológicas regula el nivel de Ca2+ luminal, pero cuando se encuentra alterada participa en la generación de arritmias adquiridas o hereditarias. Recientemente, el esfuerzo de diversos grupos de investigación se ha enfocado en el desarrollo de herramientas farmacológicas para controlar la fuga diastólica de Ca2+ que se presenta alterada en algunas enfermedades cardiacas. En esta revisión nos enfocamos en describir la participación del receptor de rianodina cardiaco en la fuga diastólica de Ca2+ así como los diversos enfoques terapéuticos que se han implementado para controlar su actividad exacerbada en la diástole.

The participation of the ionic Ca2+ release channel/ryanodine receptor in cardiac excitation-contraction coupling is well known since the late '80s, when various seminal papers communicated its purification for the first time and its identity with the "foot" structures located at the terminal cisternae of the sarcoplasmic reticulum. In addition to its main role as the Ca2+ channel responsible for the transient Ca2+ increase that activates the contractile machinery of the cardiomyocytes, the ryanodine receptor releases Ca2+ during the relaxation phase of the cardiac cycle, giving rise to a diastolic Ca2+ leak. In normal physiological conditions, diastolic Ca2+ leak regulates the proper level of luminal Ca2+, but in pathological conditions it participates in the generation of both, acquired and hereditary arrhythmias. Very recently, several groups have focused their efforts into the development of pharmacological tools to control the altered diastolic Ca2+ leak via ryanodine receptors. In this review, we focus our interest on describing the participation of cardiac ryanodine receptor in the diastolic Ca2+ leak under physiological or pathological conditions and also on the therapeutic approaches to control its undesired exacerbated activity during diastole.

Regulation of cardiac excitation-contraction coupling by sorcin, a novel modulator of ryanodine receptors

Activation of Ca2+ release channels/ryanodine receptors (RyR) by the inward Ca2+ current (ICa) gives rise to Ca2+-induced Ca2+ release (CICR), the amplifying Ca2+ signaling mechanism that triggers contraction of the heart. CICR, in theory, is a high-gain, self-regenerating process, but an unidentified mechanism stabilizes it in vivo. Sorcin, a 21.6 kDa Ca2+-binding protein, binds to cardiac RyRs with high affinity and completely inhibits channel activity. Sorcin significantly inhibits both the spontaneous activity of RyRs in quiescent cells (visualized as Ca2+ sparks) and the ICa-triggered activity of RyRs that gives rise to [Ca2+]i transients. Since sorcin decreases the amplitude of the [Ca2+]i transient without affecting the amplitude of ICa, the overall effect of sorcin is to reduce the "gain" of excitation-contraction coupling. Immunocytochemical staining shows that sorcin localizes to the dyadic space of ventricular cardiac myocytes. Ca2+ induces conformational changes and promotes translocation of sorcin between soluble and membranous compartments, but the [Ca2+] required for the latter process (ED50 = ~200 mM) appears to be reached only within the dyadic space. Thus, sorcin is a potent inhibitor of both spontaneous and ICa-triggered RyR activity and may play a role in helping terminate the positive feedback loop of CICR.