Altered State Dependence of C-Type Inactivation in the Long and Short Forms of Human Kv1.5

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Abstract
Evidence from both human and murine cardiomyocytes suggests that truncated isoforms of Kv1.5 can be expressed in vivo. Using whole-cell patch-clamp recordings, we have characterized the activation and inactivation properties of Kv1.5ΔN209, a naturally occurring short form of human Kv1.5 that lacks roughly 75% of the T1 domain. When expressed in HEK 293 cells, this truncated channel exhibited a V1/2 of −19.5 ± 0.9 mV for activation and −35.7 ± 0.7 mV for inactivation, compared with a V1/2 of −11.2 ± 0.3 mV for activation and −0.9 ± 1.6 mV for inactivation in full-length Kv.15. Kv1.5ΔN209 channels exhibited several features rarely observed in voltage-gated K+ channels and absent in full-length Kv1.5, including a U-shaped voltage dependence of inactivation and “excessive cumulative inactivation,” in which a train of repetitive depolarizations resulted in greater inactivation than a continuous pulse. Kv1.5ΔN209 also exhibited a stronger voltage dependence to recovery from inactivation, with the time to half-recovery changing e-fold over 30 mV compared with 66 mV in full-length Kv1.5. During trains of human action potential voltage clamps, Kv1.5ΔN209 showed 30–35% greater accumulated inactivation than full-length Kv1.5. These results can be explained with a model based on an allosteric model of inactivation in Kv2.1 (Klemic, K.G., C.-C. Shieh, G.E. Kirsch, and S.W. Jones. 1998. Biophys. J. 74:1779–1789) in which an absence of the NH2 terminus results in accelerated inactivation from closed states relative to full-length Kv1.5. We suggest that differential expression of isoforms of Kv1.5 may contribute to K+ current diversity in human heart and many other tissues.