The immunosuppressant drug cyclosporine A (CsA) has emerged as an important new cause of secondary hypertension and previous studies implicated a major neurogenic component in the pathogenesis. The mechanism involves inhibition of calcineurin, the Ca2+-dependent phosphatase that also mediates the immunosuppressive action of CsA. Using genetic mouse models, a recent study from our lab showed that CsA increases blood pressure and sympathetic outflow, at least acutely, by stimulating renal sensory nerve endings containing synapsins, a family of vesicle-associated phosphoproteins that constitute putative in vivo substrates for calcineurin. In mice lacking both synapsins I and II, renal sensory endings are normally developed but are unresponsive to CsA, and the resultant reflex increases in sympathetic activity and blood pressure are greatly attenuated compared with wild type. Building on these previous studies in anesthetized models, the goals of my proposal are: (1) to determine if synapsin also plays a major role in causing chronic hypertension with CsA, and (2) to determine whether synapsin I or synapsin II is the principal isoform mediating the hypertension. Both molecules contain a PKA phosphorylation site at the N-terminus; in addition, synapsin I has 5 additional MAP- kinase and CAM-kinase phosphorylation sites that are not present on synapsin II. Recent in vitro studies indicate that the MAP-kinase phosphorylation sites, located exclusively on synapsin I, constitute important calcineurin substrates, whereas the common PKA phosphorylation site is relatively insensitive to calcineurin.