Molecular pharmacological studies on potassium channels and their regulatory molecules

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 α and accessory β 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 a (Kv4.3L) and β (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 BKβ1 interacts with cytochrome c oxidase I (Cco1) in cardiac mitochondria, and that the activation of BK channels by 17β-estradiol results in a significant increase in the survival rate of ventricular myocytes. These findings suggest that BKβ1 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. © 2006 The Pharmaceutical Society of Japan.