Modeling CaMKII-mediated regulation of L-type Ca(2+) channels and ryanodine receptors in the heart

Abstract

Excitation-contraction coupling (ECC) in the cardiac myocyte is mediated by a number of highly integrated mechanisms of intracellular Ca(2+) transport. Voltage- and Ca(2+)-dependent L-type Ca(2+) channels (LCCs) allow for Ca(2+) entry into the myocyte, which then binds to nearby ryanodine receptors (RyRs) and triggers Ca(2+) release from the sarcoplasmic reticulum in a process known as Ca(2+)-induced Ca(2+) release. The highly coordinated Ca(2+)-mediated interaction between LCCs and RyRs is further regulated by the cardiac isoform of the Ca(2+)/calmodulin-dependent protein kinase (CaMKII). Because CaMKII targets and modulates the function of many ECC proteins, elucidation of its role in ECC and integrative cellular function is challenging and much insight has been gained through the use of detailed computational models. Multiscale models that can both reconstruct the detailed nature of local signaling events within the cardiac dyad and predict their functional consequences at the level of the whole cell have played an important role in advancing our understanding of CaMKII function in ECC. Here, we review experimentally based models of CaMKII function with a focus on LCC and RyR regulation, and the mechanistic insights that have been gained through their application.

Keywords: CaMKII; cardiac myocyte; cell signaling; computational modeling; excitation-contraction coupling.

Figure 1

(A) Schematic representation of the cardiac dyad. Ca²⁺ ions pass through the LCC and enter the dyad, where they bind to RyRs, triggering CICR. The activity of each CaMKII monomer is a function of dyadic Ca²⁺ levels. Ca²⁺ ions released from the SR diffuse out of the dyad into the bulk myoplasm. (B) Simulated results from a 1-Hz AP-pacing protocol under different LCC and/or RyR phosphorylation conditions. (C) APD₉₀ as a function of average LCC phosphorylation levels. Fully phosphorylated LCCs gate in mode 2, which exibit long-duration openings. (A) Reprinted with permission from Hashambhoy et al. (2009). Copyright 2009 Elsevier. (B,C) Reprinted with permission from Hashambhoy et al. (2010). Copyright 2010 Elsevier.

Figure 2

(A) State diagram of the stochastic CaMKII activation model of Foteinou et al. (2013). Prior to the introduction of Ca²⁺/CaM, all of the CaMKII subunits are in the inactive form (state I). Activation occurs upon binding of Ca²⁺/CaM (state B), autophosphorylation (state P), and oxidation (state Ox_B). Autonomous active states (Ca²⁺/CaM-unbound) can be either autophosphorylated (state A) or oxidized (state Ox_A). The model also includes an active state that is both oxidized and phosphorylated (state Ox_P). (B) Simulated steady state APs under control conditions (0 μM H₂O₂). (C) Simulated APs, some of which exhibit EADs, under conditions of elevated oxidant stress (200 μM H₂O₂). Simulated APs are from a 2 s PCL pacing protocol (ensemble of 12500 calcium release units). For each condition, results for 10 consecutive APs following an initial 10 s of pacing are shown.