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CaMKII-induced shift in modal gating explains L-type Ca(2+) current facilitation: a modeling study.

ABSTRACT: Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays an important role in L-type Ca(2+) channel (LCC) facilitation: the Ca(2+)-dependent augmentation of Ca(2+) current (I(CaL)) exhibited during rapid repeated depolarization. Multiple mechanisms may underlie facilitation, including an increased rate of recovery from Ca(2+)-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 Ca(2+) 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 I(CaL) 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 I(CaL) experiments.

SUBMITTER: Hashambhoy YL

PROVIDER: S-EPMC2717283 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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CaMKII-induced shift in modal gating explains L-type Ca(2+) current facilitation: a modeling study.

Hashambhoy Yasmin L YL Winslow Raimond L RL Greenstein Joseph L JL

Biophysical journal 20090301 5

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays an important role in L-type Ca(2+) channel (LCC) facilitation: the Ca(2+)-dependent augmentation of Ca(2+) current (I(CaL)) exhibited during rapid repeated depolarization. Multiple mechanisms may underlie facilitation, including an increased rate of recovery from Ca(2+)-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 hypo ...[more]

PMID: 19254537

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Project description:The transverse tubular system of rabbit ventricular myocytes consists of cell membrane invaginations (t-tubules) that are essential for efficient cardiac excitation-contraction coupling. In this study, we investigate how t-tubule micro-anatomy, L-type Ca(2+) channel (LCC) clustering, and allosteric activation of Na(+)/Ca(2+) exchanger by L-type Ca(2+) current affects intracellular Ca(2+) dynamics. Our model includes a realistic 3D geometry of a single t-tubule and its surrounding half-sarcomeres for rabbit ventricular myocytes. The effects of spatially distributed membrane ion-transporters (LCC, Na(+)/Ca(2+) exchanger, sarcolemmal Ca(2+) pump, and sarcolemmal Ca(2+) leak), and stationary and mobile Ca(2+) buffers (troponin C, ATP, calmodulin, and Fluo-3) are also considered. We used a coupled reaction-diffusion system to describe the spatio-temporal concentration profiles of free and buffered intracellular Ca(2+). We obtained parameters from voltage-clamp protocols of L-type Ca(2+) current and line-scan recordings of Ca(2+) concentration profiles in rabbit cells, in which the sarcoplasmic reticulum is disabled. Our model results agree with experimental measurements of global Ca(2+) transient in myocytes loaded with 50??M Fluo-3. We found that local Ca(2+) concentrations within the cytosol and sub-sarcolemma, as well as the local trigger fluxes of Ca(2+) crossing the cell membrane, are sensitive to details of t-tubule micro-structure and membrane Ca(2+) flux distribution. The model additionally predicts that local Ca(2+) trigger fluxes are at least threefold to eightfold higher than the whole-cell Ca(2+) trigger flux. We found also that the activation of allosteric Ca(2+)-binding sites on the Na(+)/Ca(2+) exchanger could provide a mechanism for regulating global and local Ca(2+) trigger fluxes in vivo. Our studies indicate that improved structural and functional models could improve our understanding of the contributions of L-type and Na(+)/Ca(2+) exchanger fluxes to intracellular Ca(2+) dynamics.

Dataset Information

CaMKII-induced shift in modal gating explains L-type Ca(2+) current facilitation: a modeling study.

Publications

CaMKII-induced shift in modal gating explains L-type Ca(2+) current facilitation: a modeling study.

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