Angiotensin II (Ang II) acts at neuronal Ang II type 1 (AT1) receptors in the hypothalamus and brainstem to stimulate numerous physiological effects including baroreflex modulation, increased blood pressure, water and salt intake and secretion of vasopressin. There is also evidence for an inhibitory role of Ang II type 2 (AT2 receptors) in some of these functions. Furthermore, the demonstration that AT1 and AT2 receptors can modulate intracellular pathways which are normally regulated by growth factor (tyrosine kinase) receptors indicates undisclosed roles of these receptor subtypes in the brain, possibly in relation to cell growth, differentiation and apoptosis. Despite the evidence for important functional roles of neuronal Ang II receptors, knowledge of the neuronal membrane ionic currents and intracellular pathways which are modulated following AT1 and AT2 receptor activation is far from complete. The present studies, using neurons cultured from newborn rat hypothalamus and brainstem have identified distinct K+ and Ca2+ currents which are modulated by AT1 and AT2 receptors, and have begun to uncover the intracellular mechanisms that are responsible for the observed changes in currents. In this proposal the PI plans to continue these studies. The overall aim is to gain a further understanding of the intracellular messengers involved in Ang II-modulated K+ and Ca2+ currents, and to determine the modulatory effects of Ang II and intracellular messengers on the K+ and Ca2+ channels which underlie these currents. Specific studies, which will utilize both whole cell and single channel voltage clamp techniques, are: (1) to define the intracellular mechanisms which are responsible for AT1 receptor-mediated changes in neuronal K+ and Ca2+ currents. (2) To define the intracellular mechanisms which are responsible for the AT2 receptor-mediated changes in neuronal K+ currents. (3) To determine the effects of AngII, via AT1 and AT2 receptors, on the biophysical properties of neuronal single K+ and Ca2+ channels, and to determine the roles of intracellular messengers in these events. The significance of these studies is that the PI will identify basic intracellular and ionic mechanisms that are involved in the physiological actions mediated by neuronal Ang II receptors. This information is essential for a full understanding of the central nervous system (CNS)-mediated effects of Ang II on the cardiovascular system, fluid intake, hormone secretion, and as yet undefined functions (differentiation, apoptosis). Furthermore, this basic information will be valuable for determining the mechanisms which underlie abnormalities of Ang II actions in the CNS.
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