This application Aims to identify receptor-mediated signaling pathways in peripheral nerve and their role in experimental diabetic neuropathy. In prior work with cultured Schwann cells, she has shown that endothelins regulate levels of cyclic AMP, inositol phosphates, and ionized calcium. She will now characterize the expression of endothelin receptors in peripheral nerve, and study changes in their expression and affinity, and in the expression of ET-1, during experimental diabetes induced in rats by strepto-zotocin. Then she will examine the signaling pathways modulated by endothelins, including the roles of G proteins, the activities of phospholipase C, adenylyl cyclase, and sodium, potassium ATPase. Finally, she will examine the effects if incubation of immortalized Schwann cells in high glucose media on basal and endothelin-driven signaling and cell proliferation, and examine the reversibility of the effects of high glucose elicited by diminishing glucose or myo-inositol supplements.