Structure-Dynamic and Regulatory Specificities of Epithelial Na+/Ca2+ Exchangers

A limited number of splice variants, derived from the three genes (NCX1–3) of the Na+/Ca2+ exchanger family (NCX), are expressed in epithelial tissues while extruding a major amount of total Ca2+ (up to 70%) from the cell. The epithelial NCX isoform/splice variants are allosterically regulated by Ca2+, Na+, and H+ ions; they exhibit different capacities for performing three major regulatory modes: (a) Ca2+-dependent activation, (b) Na+-dependent inactivation, and (c) Ca2+-induced alleviation of Na+-dependent inactivation. These allosteric modulations are mediated by two Ca2+-binding regulatory domains (CBD1 and CBD2), where the splicing segment, exclusively allocated at CBD2, diversifies the regulatory features of both CBDs. During the last decade, vast progress has been made in understanding the molecular mechanisms underlying the ion-dependent regulation of tissue-specific NCX variants. The present review focuses on the structure-dynamic determinants governing the functional and regulatory features of NCX variants expressed in different types of epithelial tissues.