Preservation of cardiac function by prolonged action potentials in mice deficient of KCHIP2

Inherited ion channelopathies and electrical remodeling in heart disease alter the cardiac action potential with important consequences for excitation-contraction coupling. Potassium channel-interacting protein 2 (KChIP2) is reduced in heart failure and interacts under physiological conditions with both Kv4 to conduct the fast-recovering transient outward K⁺ current (I_to,f) and with CaV1.2 to mediate the inward L-type Ca²⁺ current (I_Ca,L). Anesthetized KChIP2^-/- mice have normal cardiac contraction despite the lower I_Ca,L, and we hypothesized that the delayed repolarization could contribute to the preservation of contractile function. Detailed analysis of current kinetics shows that only I_Ca,L density is reduced, and immunoblots demonstrate unaltered CaV1.2 and CaVβ₂ protein levels. Computer modeling suggests that delayed repolarization would prolong the period of Ca²⁺ entry into the cell, thereby augmenting Ca²⁺-induced Ca²⁺ release. Ca²⁺ transients in disaggregated KChIP2^-/- cardiomyocytes are indeed comparable to wild-type transients, corroborating the preserved contractile function and suggesting that the compensatory mechanism lies in the Ca²⁺-induced Ca²⁺ release event. We next functionally probed dyad structure, ryanodine receptor Ca²⁺ sensitivity, and sarcoplasmic reticulum Ca²⁺ load and found that increased temporal synchronicity of the Ca²⁺ release in KChIP2^-/- cardiomyocytes may reflect improved dyad structure aiding the compensatory mechanisms in preserving cardiac contractile force. Thus the bimodal effect of KChIP2 on I_to,f and I_Ca,L constitutes an important regulatory effect of KChIP2 on cardiac contractility, and we conclude that delayed repolarization and improved dyad structure function together to preserve cardiac contraction in KChIP2^-/- mice.