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Divergent Behavioral Roles Of Angiotensin Receptor Intracellular Signaling Cascades

Derek Daniels, Daniel K. Yee, Lucy F. Faulconbridge, Steven J. Fluharty

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Central injections of angiotensin II (AngII) increase both water and NaCl intake. These effects of AngII occur largely through stimulation of the AngII type 1 (AT1) receptor. Stimulation of the AT1 receptor leads to a number of intracellular events, including phospholipase C (PLC) activation and the subsequent formation of diacylglycerol and inositol trisphosphate (IP3), which then activate protein kinase C (PKC) and increase intracellular calcium, respectively. In addition, AT1 receptor stimulation leads to the activation of MAPK family members. Recent experiments using mutated AT1 receptor constructs or the AngII analog Sar1,Ile4,Ile8-AngII (SII) revealed that MAPK activation can occur independent of PLC/PKC/IP3 activation. The present experiments used in vitro and in vivo approaches to clarify the cellular and behavioral responses to SII. Specifically, SII mimicked AngII stimulation of MAPK in AT1 receptor-transfected COS-1 cells and rat brain but blocked the effects of AngII in two distinct settings: in vitro stimulation of IP3 and in vivo increases in water intake. Moreover, SII increased intake of 1.5% NaCl, despite the SII blockade of IP3 formation and water intake. Examination of brain tissue showed increases in Fos expression in several AngII-sensitive brain areas after injection of AngII, but not SII. The lack of SII-induced IP3 production, water intake, and Fos expression strongly suggest that the PLC/PKC/IP3 pathway is required for water intake, but not NaCl consumption stimulated by AngII. Collectively, these results support the hypothesis that divergent intracellular signals from a single receptor type can give rise to separable behavioral phenomena.