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1 Departments of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada
2 Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
3 Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada
4 Division of Stroke and Vacular Disease, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada
* To whom correspondence should be addressed. E-mail: gpierce{at}sbrc.ca.
The sodium-calcium exchanger (NCX1) exhibits tissue-specific alternative splicing. Certain NCX splice variants such as NCX1.1 and NCX1.3 are also differentially regulated by Na+ and Ca2+ although the physiological implications of these regulatory characteristics are unclear. Based on these distinct regulatory profiles, we hypothesized that cells expressing different splice variants might exhibit unique responses to conditions promoting Ca2+ overload such as during exposure to cardiac glycosides or simulated ischemia. NCX 1.1 or NCX1.3 were expressed in HEK293 cells or neonatal rat cardiomyocytes. Expression was confirmed by Western blotting and immunocytochemical analyses. HEK293 cells lacked NCX1 protein prior to transfection. Using adenoviral vectors, neonatal cardiomyocytes were induced to over-express the NCX1.1 splice variant by ~2 fold whereas the NCX1.3 isoform was expressed on an endogenous NCX1.1 background. Total expression for NCX1.1 and NCX1.3 was comparable. Exposure of neonatal cardiomyocytes to ouabain induced a significant increase in cellular Ca2+, an effect that was exaggerated in the cells over-expressing NCX1.1 but not for those expressing NCX1.3. The increase in intracellular Ca2+ was inhibited by 5 µM KB-R7943. Cardiomyocytes over-expressing NCX1.1 also exhibited a greater accumulation of Ca2+i in response to simulated ischemia than did cells expressing NCX 1.3. Similar responses were observed in HEK293 cells where NCX1.1 was expressed. We conclude that expression of the NCX1.3 splice variant protects against severe Ca2+ overload, whereas NCX1.1 promotes Ca2+ overload in response to cardiac glycosides and ischemic challenges. These results highlight the importance of ionic regulation in controlling NCX1 activity under conditions promoting Ca2+ overload.
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