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2-ISOFORM SPECIFICALLY COUPLES TO CONTRACTILITY IN VASCULAR SMOOTH MUSCLE: EVIDENCE FROM GENE-TARGETED NEONATAL MICE
1 Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
2 Biochemistry, Microbiology and Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
3 Physiology, University of Arizona, Tucson, AZ, USA
* To whom correspondence should be addressed. E-mail: Richard.Paul{at}uc.edu.
The relative expression of the 
1- and 2-Na+,K+-ATPase isoforms found in vascular smooth muscle is developmentally regulated and under hormonal and neurogenic control. The physiological role of these isoforms in vascular function is not known. It has been postulated that 1 serves a "housekeeping" role, whereas 2 localizes to a subsarcolemmal compartment and modulates contractility. To test this hypothesis, isoform specific, gene-targeted mice, in which the mRNA for either the 1 or 2 Na+,K+-ATPase isoform was ablated (18), were utilized. Both knockouts, 1-/- and 2-/- are lethal, the latter dies at birth but this allows this neonatal aorta to be studied. Isometric force in 2-/- aorta was more sensitive to contractile agonists and less sensitive to the vasodilators, forskolin and sodium nitroprusside, than wild type (WT); 2+/- aortas were intermediate. In contrast, neonatal 1+/- was similar to WT. Western Blot analysis indicated a population of 70% 1 and 30% 2, in the WT. Thus in terms of the total Na+,K+-ATPase protein, the 2-/- (70%) would be similar to the 1+/- aorta (65%), but with a dramatically different phenotype. These data suggest that individual -isoforms of the Na+,K+-ATPase differ functionally with the 2-isoform more strongly coupled to activation/relaxation pathways. Three-dimensional image acquisition and deconvolution analysis suggests that the 2 isoform is distributed differently than the 1 isoform. Importantly, these isoforms do not localize to the same regions.
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