TY - JOUR
T1 - Dynamics of calcium sparks and calcium leak in the heart
AU - Williams, George S.B.
AU - Chikando, Aristide C.
AU - Tuan, Hoang Trong M.
AU - Sobie, Eric A.
AU - Lederer, W. J.
AU - Jafri, M. Saleet
N1 - Funding Information:
We acknowledge support from National Science Foundation DMS-0443843; National Institutes of Health 01 HL67849, R01 HL36974, F32 HL108604, and S10 RR023028; the Leducq North American-European Atrial Fibrillation Research Alliance; the European Union Seventh Framework Program (FP7); the Georg-August University “Identification and Therapeutic Targeting of Common Arrhythmia Trigger Mechanisms” program; and the Maryland Stem Cell Research Fund.
PY - 2011/9/21
Y1 - 2011/9/21
N2 - We present what we believe to be a new mathematical model of Ca 2+ leak from the sarcoplasmic reticulum (SR) in the heart. To our knowledge, it is the first to incorporate a realistic number of Ca 2+-release units, each containing a cluster of stochastically gating Ca 2+ channels (RyRs), whose biophysical properties (e.g., Ca 2+ sensitivity and allosteric interactions) are informed by the latest molecular investigations. This realistic model allows for the detailed characterization of RyR Ca 2+-release properties, and shows how this balances reuptake by the SR Ca 2+ pump. Simulations reveal that SR Ca 2+ leak consists of brief but frequent single RyR openings (∼3000 cell -1 s -1) that are likely to be experimentally undetectable, and are, therefore, "invisible". We also observe that these single RyR openings can recruit additional RyRs to open, due to elevated local (Ca 2+), and occasionally lead to the generation of Ca 2+ sparks (∼130 cell -1 s -1). Furthermore, this physiological formulation of "invisible" leak allows for the removal of the ad hoc, non-RyR mediated Ca 2+ leak terms present in prior models. Finally, our model shows how Ca 2+ sparks can be robustly triggered and terminated under both normal and pathological conditions. Together, these discoveries profoundly influence how we interpret and understand diverse experimental and clinical results from both normal and diseased hearts.
AB - We present what we believe to be a new mathematical model of Ca 2+ leak from the sarcoplasmic reticulum (SR) in the heart. To our knowledge, it is the first to incorporate a realistic number of Ca 2+-release units, each containing a cluster of stochastically gating Ca 2+ channels (RyRs), whose biophysical properties (e.g., Ca 2+ sensitivity and allosteric interactions) are informed by the latest molecular investigations. This realistic model allows for the detailed characterization of RyR Ca 2+-release properties, and shows how this balances reuptake by the SR Ca 2+ pump. Simulations reveal that SR Ca 2+ leak consists of brief but frequent single RyR openings (∼3000 cell -1 s -1) that are likely to be experimentally undetectable, and are, therefore, "invisible". We also observe that these single RyR openings can recruit additional RyRs to open, due to elevated local (Ca 2+), and occasionally lead to the generation of Ca 2+ sparks (∼130 cell -1 s -1). Furthermore, this physiological formulation of "invisible" leak allows for the removal of the ad hoc, non-RyR mediated Ca 2+ leak terms present in prior models. Finally, our model shows how Ca 2+ sparks can be robustly triggered and terminated under both normal and pathological conditions. Together, these discoveries profoundly influence how we interpret and understand diverse experimental and clinical results from both normal and diseased hearts.
UR - http://www.scopus.com/inward/record.url?scp=80053109641&partnerID=8YFLogxK
U2 - 10.1016/j.bpj.2011.07.021
DO - 10.1016/j.bpj.2011.07.021
M3 - Article
C2 - 21943409
AN - SCOPUS:80053109641
SN - 0006-3495
VL - 101
SP - 1287
EP - 1296
JO - Biophysical Journal
JF - Biophysical Journal
IS - 6
ER -