title: mTORC1 Signaling Contributes to Drinking But Not Blood Pressure Responses to Brain Angiotensin II.
abstract: Mechanistic target of rapamycin complex 1 (mTORC1) is a molecular node that couples extracellular cues to a wide range of cellular events controlling various physiological processes. Here, we identified mTORC1 signaling as a critical mediator of angiotensin II (Ang II) action in the brain. In neuronal GT1-7 cells, we show that Ang II stimulates neuronal mTORC1 signaling in an Ang II type 1 receptor-dependent manner. In mice, a single intracerebroventricular (ICV) injection or chronic sc infusion of Ang II activated mTORC1 signaling in the subfornical organ, a critical brain region in cardiovascular control and fluid balance. Moreover, transgenic sRA mice with brain-specific overproduction of Ang II displayed increased mTORC1 signaling in the subfornical organ. To test the functional role of brain mTORC1 in mediating the action of Ang II, we examined the consequence of mTORC1 inhibition with rapamycin on Ang II-induced increase in water intake and arterial pressure. ICV pretreatment with rapamycin blocked ICV Ang II-mediated increases in the frequency, duration, and amount of water intake but did not interfere with the pressor response evoked by Ang II. In addition, ICV delivery of rapamycin significantly reduced polydipsia, but not hypertension, of sRA mice. These results demonstrate that mTORC1 is a novel downstream pathway of Ang II type 1 receptor signaling in the brain and selectively mediates the effect of Ang II on drinking behavior.
authors.affiliation: Department of Pharmacology (K.M., D.A.M., J.L.G., C.D.S., K.R.), University of Iowa Healthcare Center for Hypertension Research (J.L.G., C.D.S., K.R.), and Fraternal Order of Eagles Diabetes Research Center (J.L.G., C.D.S., K.R.), University of Iowa, Iowa City, Iowa 52242.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Muta
authors.affiliation: Department of Pharmacology (K.M., D.A.M., J.L.G., C.D.S., K.R.), University of Iowa Healthcare Center for Hypertension Research (J.L.G., C.D.S., K.R.), and Fraternal Order of Eagles Diabetes Research Center (J.L.G., C.D.S., K.R.), University of Iowa, Iowa City, Iowa 52242.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Morgan
authors.affiliation: Department of Pharmacology (K.M., D.A.M., J.L.G., C.D.S., K.R.), University of Iowa Healthcare Center for Hypertension Research (J.L.G., C.D.S., K.R.), and Fraternal Order of Eagles Diabetes Research Center (J.L.G., C.D.S., K.R.), University of Iowa, Iowa City, Iowa 52242.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
authors.affiliation: Department of Pharmacology (K.M., D.A.M., J.L.G., C.D.S., K.R.), University of Iowa Healthcare Center for Hypertension Research (J.L.G., C.D.S., K.R.), and Fraternal Order of Eagles Diabetes Research Center (J.L.G., C.D.S., K.R.), University of Iowa, Iowa City, Iowa 52242.
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.affiliation: Department of Pharmacology (K.M., D.A.M., J.L.G., C.D.S., K.R.), University of Iowa Healthcare Center for Hypertension Research (J.L.G., C.D.S., K.R.), and Fraternal Order of Eagles Diabetes Research Center (J.L.G., C.D.S., K.R.), University of Iowa, Iowa City, Iowa 52242.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004326:Drinking / Q000187:drug effects / Q000235:genetics; D004327:Drinking Behavior / Q000187:drug effects; D005260:Female; D007276:Injections, Intraventricular; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: D046912:Multiprotein Complexes; D000804:Angiotensin II; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases