The Na⁺ HCO₃^- cotransporter (NBC) family plays an essential role in cellular acid-base homeostasis throughout the body. Ubiquitous expression of the NBC family suggests a role in cell pH regulation; however, the exact role and function of this transporter in most tissues is not clear. Two tissues which have been shown to rely heavily on the presence of NBC are those of the kidney and salivary glands. The electrogenic NBC (NBCe1) has been studied extensively in the kidney and is involved in HCO₃^- reabsorption. Within the parotid gland, NBCe1 and the electroneutral NBCn1 have been localized using functional studies and antibodies. The details underlying the regulation of these transporters in both kidney and parotid gland are not known. In the following, studies I have examined the mechanisms of regulation of the NBCe1 and electroneutral NBC (NBCn1) in Xenopus oocytes and parotid acinar (ParC5) cells. My fundamental research questions are: (1) Does inhibition of NBC involve specific PKC isoforms? and (2) Is regulation of NBC due to changes in the number of transporters at the cell surface? I have examined these questions through use of biotinylation, coimmunoprecipitation, two electrode voltage-clamp technique and confocal fluorescence microscopy in both Xenopus oocytes and ParC5 cells. My results demonstrate that both an agonist of PKC, phorbol myristate acetate (PMA), and angiotensin II (ANGII) inhibit NBCe1 activity in Xenopus oocytes. ANGII, through a PKC&epsis; dependent pathway, inhibits NBCe1 activity via endocytosis, while Ca⁺/CaM/CaMKII regulate membrane expression of NBCe1 via inhibition of constitutively recycling transporter to the cell surface. In other studies in ParC5 cells cholinergic stimulation causes PKCS-dependent endocytosis of both renal and pancreas variants of NBCe1 (NBCe1-A and B, respectively). However, I found no effect from cholinergic stimulation on the surface expression of the electroneutral NBC (NBCn1). NBCn1 seems to exhibit a very low rate of constitutive endocytosis in ParC5 cells. Collectively, my work has revealed a novel form of regulation of NBC activity and has identified specific targets of regulation of NBC activity.