Tissue‐Specific Modes of Na/Ca Exchanger Regulation

Ionic regulation of Na(+)/Ca(2+) exchange describes the secondary modulating effects exerted on exchange activity by the transport substrates Na(+) and Ca(2+). These effects have been extensively characterized for the cardiac Na(+)/Ca(2+) exchanger, NCX1.1, primarily by the giant excised patch-clamp technique. Moreover, several studies have provided functional evidence for ionic regulation of Na(+)/Ca(2+) exchange activity in intact cellular systems. Through structure-function analyses, important protein domains involved in these regulatory processes have been identified. However, despite major progress in characterizing ionic regulation at the functional and molecular levels, the physiological importance of these processes remains unknown. In this study, we have examined Na(+)/Ca(2+) exchange activity for three members of the NCX1 family, namely NCX1.1, NCX1.3, and NCX1.4. These exchangers were expressed in Xenopus laevis oocytes and were characterized using the giant excised patch-clamp technique. We show that these three splice variants exhibit considerable differences in the kinetic features of their ionic regulatory profiles. Information of this type is beginning to provide insight into the physiological basis for tissue-specific expression of alternatively spliced Na(+)/Ca(2+) exchangers.