Most significant result of IMPG SAS in 2015 in international collaboration

The Scientific Board of IMPG SAS evaluated as the most significant result of 2015 in the field of international collaboration the work by authors P. Petrovič, I. Valent, E. Cocherová, J. Pavelková, A. Zahradníková:

Ryanodine receptor controls formation of calcium waves in cardiac myocytes

During heart contraction (systole), a large amount of calcium enters from intracellular stores into the cytoplasm through open ryanodine receptors (RyR). Upon relaxation (during the diastole) it is necessary to stop the calcium leak, i.e., to close the RyRs. Therefore, opening and closing of ryanodine receptors is subject to accurate regulation. Many heart diseases are characterized by increased calcium leak into the cytoplasm during diastole, resulting in formation of calcium waves and subsequent cardiac arrhythmias. We have found that dysregulation of RyRs leads to formation of calcium waves when the probability that spontaneous activation of a ryanodine receptor at one site triggers activation of a RyR at a neighbouring calcium release site. Formation of waves depends steeply on the concentration of calcium ions in the lumen of the sarcoplasmic reticulum. We found that facilitation of calcium binding to the cytosolic activation site of RyR may be paradoxically manifested as an increase in the sensitivity of RyRs to luminal calcium concentration. We have shown that defects of diverse regulatory sites of the ryanodine receptor can be eliminated by reducing the likelihood of spontaneous, calcium-independent activation of the RyR. Spontaneous activation of ryanodine receptor could therefore be a suitable target for pharmacotherapy of the relevant types of arrhythmias.

A scheme of calcium wave formation. Under normal conditions, calcium wave formation does not occur (middle figure) and calcium concentration in the lumen of sarcoplasmic reticulum does not change (black line). Increasing luminal calcium leads to formation of waves (top figure) and to temporary depletion of calcium stores (red line). When binding of cytosolic Ca2+ to the RyR activation site is facilitated, waves are formed already at a reduced luminal Ca2+ concentration (lower image, blue line).

Projects:LSHM-CT-2005-018802/CONTICA, LSHM-CT-2005-018833/EUGeneHeart, ESF program FUNCDYN, APVV-0721-10, VEGA 2/0148/14

Publication: PETROVIČ, Pavol – VALENT, Ivan*COCHEROVÁ, Elena*PAVELKOVÁ, JanaZAHRADNÍKOVÁ, Alexandra. Ryanodine receptor gating controls generation of diastolic calcium waves in cardiac myocytes. In Journal of General Physiology, 2015, vol. 145, no. 6, p. 489-511. (4.788 – IF2014). (2015 – Current Contents). ISSN 0022-1295

*Researchers employed at IMPG SAS for the projects CONTICA and EUGeneHeart