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Divergent Behavioral Roles of Angiotensin Receptor Intracellular Signaling Cascades

Departments of Animal Biology (D.D., D.K.Y., S.J.F.), Psychology (L.F.F., S.J.F.), and Pharmacology (S.J.F.) and the Institute of Neurological Sciences (S.J.F.), University of Pennsylvania, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Daniel Yee, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, 220E, Philadelphia, Pennsylvania 19104. E-mail: dkyee{at}vet.upenn.edu.

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.

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