Renal production and excretion of NH3/NH4+ play a vital role in acid/base homeostasis and regulation of systemic pH. The classical model of NH3/NH4+ transport proposes that: 1) NH3 crosses cell membranes solely by non-ionic diffusion through the lipid phase of the membrane and 2) NH4+ transport occurs via channels (e.g., K+ channels) or transporters (e.g. Na/K/2CI co-transport or Na-H exchange), mostly as a substitute for K+. Recent studies report new characteristics of NH3/NH4+ transport and regulation that were not previously recognized. A new class of recently cloned membrane proteins, belonging to the Rh antigen family, may function as transporters of NH4+. Other studies indicate that NH3 transport may be facilitated by the presence of water channels (AQP). In addition, NH3 was reported to act as a signaling molecule and recent studies proposed that the Rh proteins may actually be gas channels for NH3 and even CO2. The main objectives of this proposal are to investigate the characteristics of AQPs and Rh glycoproteins with respect to NH3 and NH4+ transport. Specifically we will address the following aims: 1) Transport of NH3 through carrier proteins and the role of AQPs. 2) Characterization of transport properties of Rh glycoproteins. These studies will involve expression of cloned genes (Rh and AQPs) in oocytes to study their transport characteristics. Measurements of intracellular pH and other ions will be obtained by microelectrodes and pH sensitive dyes. Studies will also be conducted on cells in culture and the isolated perfused tubule preparation. Because of the importance of NH3/NH4+ in regulating pH, these studies have significant physiological implications. The possibility that a gas, such as NH3, could be transported through an AQP or another carrier protein, is unique and suggest that its transport could be regulated. NH4+-specific transporters, as Rh glycoproteins may be, have never been described in mammalian cells before. These are new properties of NH3/NH4+ transport that will help explain the role of NH3 and NH4+ in acidosis and their effect on transport of other ions a well.
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