title: Divergent behavioral roles of angiotensin receptor intracellular signaling cascades.
abstract: 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 (AT(1)) receptor. Stimulation of the AT(1) receptor leads to a number of intracellular events, including phospholipase C (PLC) activation and the subsequent formation of diacylglycerol and inositol trisphosphate (IP(3)), which then activate protein kinase C (PKC) and increase intracellular calcium, respectively. In addition, AT(1) receptor stimulation leads to the activation of MAPK family members. Recent experiments using mutated AT(1) receptor constructs or the AngII analog Sar(1),Ile(4),Ile(8)-AngII (SII) revealed that MAPK activation can occur independent of PLC/PKC/IP(3) 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 AT(1) receptor-transfected COS-1 cells and rat brain but blocked the effects of AngII in two distinct settings: in vitro stimulation of IP(3) and in vivo increases in water intake. Moreover, SII increased intake of 1.5% NaCl, despite the SII blockade of IP(3) 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 IP(3) production, water intake, and Fos expression strongly suggest that the PLC/PKC/IP(3) 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.
authors.affiliation: Department of Animal Biology, University of Pennsylvania, Philadelphia, 19104, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Daniels
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Yee
authors.forename: Lucy F
authors.initials: LF
authors.lastname: Faulconbridge
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fluharty
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004326:Drinking / Q000187:drug effects; D007276:Injections, Intraventricular; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D012965:Sodium Chloride; D014162:Transfection; D014867:Water
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D016760:Proto-Oncogene Proteins c-fos; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; C502020:angiotensin II, Sar(1)-Ile(4)-Ile(8)-; D014867:Water; D000804:Angiotensin II; D012965:Sodium Chloride; D015544:Inositol 1,4,5-Trisphosphate; D020928:Mitogen-Activated Protein Kinases