TY - JOUR
T1 - CaMKII-induced shift in modal gating explains L-type Ca2+ current facilitation
T2 - A modeling study
AU - Hashambhoy, Yasmin L.
AU - Winslow, Raimond L.
AU - Greenstein, Joseph L.
N1 - Funding Information:
This work was supported by National Heart, Lung, and Blood Institute Grant N01-HV-28180 and National Institutes of Health Grants R33HL87345 and 1P01 HL077180.
PY - 2009
Y1 - 2009
N2 - Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays an important role in L-type Ca2+ channel (LCC) facilitation: the Ca 2+-dependent augmentation of Ca2+ current (I CaL) exhibited during rapid repeated depolarization. Multiple mechanisms may underlie facilitation, including an increased rate of recovery from Ca2+-dependent inactivation and a shift in modal gating distribution from mode 1, the dominant mode of LCC gating, to mode 2, a mode in which openings are prolonged. We hypothesized that the primary mechanism underlying facilitation is the shift in modal gating distribution resulting from CaMKII-mediated LCC phosphorylation. We developed a stochastic model describing the dynamic interactions among CaMKII, LCCs, and phosphatases as a function of dyadic Ca2+ and calmodulin levels, and we incorporated it into an integrative model of the canine ventricular myocyte. The model reproduces behaviors at physiologic protein levels and allows for dynamic transition between modes, depending on the LCC phosphorylation state. Simulations showed that a CaMKII-dependent shift in LCC distribution toward mode 2 accounted for the ICaL positive staircase. Moreover, simulations demonstrated that experimentally observed changes in LCC inactivation and recovery kinetics may arise from modal gating shifts, rather than from changes in intrinsic inactivation properties. The model therefore serves as a powerful tool for interpreting ICaL experiments.
AB - Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays an important role in L-type Ca2+ channel (LCC) facilitation: the Ca 2+-dependent augmentation of Ca2+ current (I CaL) exhibited during rapid repeated depolarization. Multiple mechanisms may underlie facilitation, including an increased rate of recovery from Ca2+-dependent inactivation and a shift in modal gating distribution from mode 1, the dominant mode of LCC gating, to mode 2, a mode in which openings are prolonged. We hypothesized that the primary mechanism underlying facilitation is the shift in modal gating distribution resulting from CaMKII-mediated LCC phosphorylation. We developed a stochastic model describing the dynamic interactions among CaMKII, LCCs, and phosphatases as a function of dyadic Ca2+ and calmodulin levels, and we incorporated it into an integrative model of the canine ventricular myocyte. The model reproduces behaviors at physiologic protein levels and allows for dynamic transition between modes, depending on the LCC phosphorylation state. Simulations showed that a CaMKII-dependent shift in LCC distribution toward mode 2 accounted for the ICaL positive staircase. Moreover, simulations demonstrated that experimentally observed changes in LCC inactivation and recovery kinetics may arise from modal gating shifts, rather than from changes in intrinsic inactivation properties. The model therefore serves as a powerful tool for interpreting ICaL experiments.
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U2 - 10.1016/j.bpj.2008.11.055
DO - 10.1016/j.bpj.2008.11.055
M3 - Article
C2 - 19254537
AN - SCOPUS:65549160090
SN - 0006-3495
VL - 96
SP - 1770
EP - 1785
JO - Biophysical journal
JF - Biophysical journal
IS - 5
ER -