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* To whom correspondence should be addressed. E-mail: juliusa{at}bcm.tmc.edu.
We have shown earlier that low concentrations of ouabain that do not perturb the ionic milieu can initiate proliferation of vascular smooth muscle cells in the synthetic phenotype(vsmc) from three different species, canine, rodent and human. This effect occurs by activation of Src and epidermal growth factor receptor (EGFR), and thus supports the concept of an additional, , non ionic, transducing function of the Na pump. The current paper presents data suggesting that such activation occurs through specific Na pump sites localized to the caveolae, and subsequent interactions with selected signaling proteins resident within the same membrane microdomain.
Our data show that at rest, 30% of the total number of Na pumps are concentrated within the caveolae. When the various vsmc are treated with proliferating concentrations of ouabain, key protein content in isolated caveolae was increased. However, the recruited proteins were different between the different tissues. Thus ouabain activated the recruitment of both the Na pump 
1 subunit and EGFR in the caveolae from rat A7r5 cells, while in both the human and canine cells, ouabain activated the recruitment of Src, with the caveolar content of the other proteins remaining constant.
These data demonstrate that ouabain interacts with the 1 subunit of the Na pump that resides within the caveolar domain, and such interaction selectively recruits signal transducing proteins to this microdomain resulting in their activation which is necessary for the initiation of the proliferative cascade.
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