Calcium/calmodulin-dependent kinase II regulation of cardiac ion channels

Abstract

Calcium/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase expressed abundantly in the heart. CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias. In this review, we summarize the modulatory effects of CaMKII on cardiac ion channel function and expression and illustrate potential implications in the onset of arrhythmias via a computer model.

Figure 1

CaMKII influences EC coupling by affecting several electrical and Ca handling proteins, including phospholamban (PLB), SR Ca release channels (RyR), and L-type Ca channels responsible for transarcolemmal Ca influx (I_CaL). In addition, Na channels (responsible for I_Na) and K channels (e.g., I_to and I_K1) have shown to be regulated by CaMKII. By exerting multiple effects on these numerous targets CaMKII can simultaneously favor heart failure and arrhythmias.

Figure 2

Modulation of Na current gating upon adenoviral CaMKIIδ_C overexpression (vs. control β-galactosidase) in adult rabbit ventricular myocytes. Experimental data by Wagner et al. (35) and simulated results with our model (4) are reported. With CaMKII I_Na availability is shifted towards more negative potentials, whereas activation is unchanged (A), more I_Na accumulates in intermediate inactivation (B), I_Na recovers more slowly from inactivation (C) and there is more sustained current upon prolonged depolarization (D). Modified from ref. (4).

Figure 3

Simulated APs at 1 Hz in βGal and CaMKIIδ_C-overexpressing cardiac myocytes in the presence of 100% (A, left) 25% (A, middle), and 10% (A, right) I_to. When I_to is fully expressed (A, epi or control), CaMKII shortens the AP, whereas the AP is prolonged due to I_to downregulation (e.g., endo or HF). This could amplify transmural dispersion of repolarization (B, endo-epi: 78 ms for βGal vs. 183 ms for CaMKII), which may predispose cells to reentry phenomena. Modified from ref. (4).

Figure 4

(A) Stimulation of steady-state AP and Ca transients followed by a period of rest in digital HF cell (left) and with isoproterenol (right) at 1 Hz. In isoproterenol cessation of 1-Hz stimulation, leads to spontaneous SR Ca release (right, lower panel) activating inward I_NCX, which depolarizes the membrane generating DADs (right, upper panel). DADs were not seen in HF (left).