title: Ca(2+) regulation in the Na(+)/Ca (2+) exchanger features a dual electrostatic switch mechanism.
abstract: Ion transport performed by the Na(+)/Ca(2+) exchanger (NCX) is regulated via its cytosolic Ca(2+)-binding domains, CBD1 and CBD2, which act as sensors for intracellular Ca(2+). Striking differences in the electrostatic potential of the Ca(2+)-bound and Ca(2+)-free forms turn the CBD1 and CBD2 Ca(2+)-binding sites into electrostatic switches similar to those of C(2) domains. Binding of Ca(2+) with high affinity to CBD1 induces a conformational change that is relayed to the transmembrane domain and thereby initiates Na(+)/Ca(2+) exchange. The Ca(2+) concentration at which this conformational change occurs is determined by the Ca(2+) affinities of the strictly conserved CBD1 Ca(2+)-binding sites that are modulated by an adjacent, variable region of CBD2. In contrast, the Ca(2+)-binding properties of CBD2 depend on the isoform and the type of residues in the Ca(2+)-binding sites, encoded by a mutually exclusive exon. This second electrostatic switch, formed by CBD2, appears to be required for sustained Na(+)/Ca(2+) exchange and may allow tailored, tissue-specific exchange activities.
authors.affiliation: University Basel, Basel, Switzerland. mark.hilge@unibas.ch
authors.forename: Mark
authors.initials: M
authors.lastname: Hilge
mesh_terms: D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport / Q000502:physiology; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012964:Sodium / Q000737:chemistry* / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity
chemical_list: D020033:Protein Isoforms; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium