title: Forefront of Na+/Ca2+ exchanger studies: molecular pharmacology of Na+/Ca2+ exchange inhibitors.
abstract: The Na+/Ca2+ exchanger (NCX) is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+ efflux or Ca2+ influx mode, depending on membrane potential and transmembrane ion gradients. In myocytes, neurons, and nephron cells, NCX is thought to play an important role in the regulation of intracellular Ca2+ concentration. Recently, the benzyloxyphenyl derivatives KB-R7943, SEA0400, and SN-6 have been developed as selective NCX inhibitors. Currently, SEA0400 is the most potent and selective inhibitor. These inhibitors possess different isoform-selectivities, although they have similar properties, such as Ca2+ influx mode-selectivity and I1 inactivation-dependence. Recent site-directed mutagenesis has revealed that these inhibitors possess some molecular determinants (Phe-213, Val-227, Tyr-228, Gly-833, and Asn-839) for interaction with NCX1. These benzyloxyphenyl derivatives are expected to be useful tools to study the physiological roles of NCX. Moreover, such inhibitors may have therapeutic potential as a new remedy for ischemic disease, arrhythmias, heart failure, and hypertension.
authors.affiliation: Department of Pharmacology, School of Medicine, Fukuoka University, Japan. tiwamoto@cis.fukuoka-u.ac.jp
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwamoto
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger