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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Conformational changes of a Ca²⁺-binding domain of the Na⁺/Ca²⁺ exchanger monitored by FRET in transgenic zebrafish heart

Departments of ¹Physiology, ²Medicine, and ³Molecular, Cell, and Developmental Biology, and the Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California

Submitted 27 March 2008 ; accepted in final form 9 June 2008

The Na⁺/Ca²⁺ exchanger is the major Ca²⁺ extrusion mechanism in cardiac myocytes. The activity of the cardiac Na⁺/Ca²⁺ exchanger is dynamically regulated by intracellular Ca²⁺. Previous studies indicate that Ca²⁺ binding to a high-affinity Ca²⁺-binding domain (CBD1) in the large intracellular loop is involved in regulation. We generated transgenic zebrafish with cardiac-specific expression of CBD1 linked to yellow and cyan fluorescent protein. Ca²⁺ binding to CBD1 induces conformational changes, as detected by fluorescence resonance energy transfer. With this transgenic fish model, we were able to monitor conformational changes of the Ca²⁺ regulatory domain of Na⁺/Ca²⁺ exchanger in intact hearts. Treatment with the positive inotropic agents ouabain and isoproterenol increased both Ca²⁺ transients and Ca²⁺-induced changes in fluorescence resonance energy transfer. The results indicate that Ca²⁺ regulation of the Na⁺/Ca²⁺ exchanger domain CBD1 changes with inotropic state. The transgenic fish models will be useful to further characterize the regulatory properties of the Na⁺/Ca²⁺ exchanger in vivo.

Ca²⁺-binding domain; sodium/calcium exchange; zebrafish; fluorescence resonance energy transfer

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