K<sup>+</sup>チャネルとその機能制御因子の分子薬理学的研究

Abstract

K+ channels play important roles in the control of a large variety of physiological functions such as muscle contraction, neurotransmitter release, hormone secretion, and cell proliferation. Over 100 cloned K+ channel pore-forming alpha and accessory beta subunits have been identified so far. Here, we introduce a series of molecular pharmacological and physiological studies on some types of voltage-dependent K+ channels and Ca2+-activated K+ channels. We examined molecular cloning and functional characterization of novel, fast-inactivating, A-type K+ channel alpha (Kv4.3L) and beta (KChIP2S) subunits predominantly expressed in mammalian heart and found the sites in Kv4 channels for 1) the regulation of voltage dependency and 2) the CaMKII phosphorylation in the C-terminal cytoplasmic domain. Moreover, we found that delayed rectifier-type K+ channels (ERG1 and KCNQ) contribute to the resting membrane conductance in vascular and gastrointestinal smooth muscles. The large-conductance Ca2+-activated K+ (BK) channel is ubiquitously expressed and contributes to diverse physiological processes. Recent reports have shown that a BK-like channel (mitoKCa) is expressed in cardiac mitochondria, suggesting that BK channel openers protect mammalian hearts against ischemic injury. Our studies revealed that BKbeta1 interacts with cytochrome c oxidase I (Cco1) in cardiac mitochondria, and that the activation of BK channels by 17beta-estradiol results in a significant increase in the survival rate of ventricular myocytes. These findings suggest that BKbeta1 may play an important role in the regulation of cell respiration in cardiac myocytes and be a target for the modulation by female gonadal hormones.