Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice.
It is known that angiotensin-II acts at its type-1 receptor to stimulate vasopressin (AVP) secretion, which may contribute to angiotensin-II-induced hypertension. Less well known is the impact of angiotensin type-2 receptor (AT2R) activation on these processes. Studies conducted in a transgenic AT2R enhanced green fluorescent protein reporter mouse revealed that although AT2R are not themselves localized to AVP neurons within the paraventricular nucleus of the hypothalamus (PVN), they are localized to neurons that extend processes into the PVN. In the present set of studies, we set out to characterize the origin, phenotype, and function of nerve terminals within the PVN that arise from AT2R-enhanced green fluorescent protein-positive neurons and synapse onto AVP neurons. Initial experiments combined genetic and neuroanatomical techniques to determine that γ-aminobutyric acid (GABA)ergic neurons derived from the peri-PVN area containing AT2R make appositions onto AVP neurons within the PVN, thereby positioning AT2R to negatively regulate neuroendocrine secretion. Subsequent patch-clamp electrophysiological experiments revealed that selective activation of AT2R in the peri-PVN area using compound 21 facilitates inhibitory (ie, GABAergic) neurotransmission and leads to reduced activity of AVP neurons within the PVN. Final experiments determined the functional impact of AT2R activation by testing the effects of compound 21 on plasma AVP levels. Collectively, these experiments revealed that AT2R expressing neurons make GABAergic synapses onto AVP neurons that inhibit AVP neuronal activity and suppress baseline systemic AVP levels. These findings have direct implications in the targeting of AT2R for disorders of AVP secretion and also for the alleviation of high blood pressure.
Department of Physiology and Functional Genomics (A.D.d.K., D.J.P., C.S.), College of Medicine, University of Florida, Gainesville, Florida 32610; Physiology (S.P., J.E.S.), Medical College of Georgia, Augusta University, Augusta, Georgia 30912; and Department of Pharmacodynamics (L.W., H.H., J.A.S., E.G.K.)., College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Annette D
AD
de Kloet
Department of Physiology and Functional Genomics (A.D.d.K., D.J.P., C.S.), College of Medicine, University of Florida, Gainesville, Florida 32610; Physiology (S.P., J.E.S.), Medical College of Georgia, Augusta University, Augusta, Georgia 30912; and Department of Pharmacodynamics (L.W., H.H., J.A.S., E.G.K.)., College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Soledad
S
Pitra
Department of Physiology and Functional Genomics (A.D.d.K., D.J.P., C.S.), College of Medicine, University of Florida, Gainesville, Florida 32610; Physiology (S.P., J.E.S.), Medical College of Georgia, Augusta University, Augusta, Georgia 30912; and Department of Pharmacodynamics (L.W., H.H., J.A.S., E.G.K.)., College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Lei
L
Wang
Department of Physiology and Functional Genomics (A.D.d.K., D.J.P., C.S.), College of Medicine, University of Florida, Gainesville, Florida 32610; Physiology (S.P., J.E.S.), Medical College of Georgia, Augusta University, Augusta, Georgia 30912; and Department of Pharmacodynamics (L.W., H.H., J.A.S., E.G.K.)., College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Helmut
H
Hiller
Department of Physiology and Functional Genomics (A.D.d.K., D.J.P., C.S.), College of Medicine, University of Florida, Gainesville, Florida 32610; Physiology (S.P., J.E.S.), Medical College of Georgia, Augusta University, Augusta, Georgia 30912; and Department of Pharmacodynamics (L.W., H.H., J.A.S., E.G.K.)., College of Pharmacy, University of Florida, Gainesville, Florida 32610.
David J
DJ
Pioquinto
Department of Physiology and Functional Genomics (A.D.d.K., D.J.P., C.S.), College of Medicine, University of Florida, Gainesville, Florida 32610; Physiology (S.P., J.E.S.), Medical College of Georgia, Augusta University, Augusta, Georgia 30912; and Department of Pharmacodynamics (L.W., H.H., J.A.S., E.G.K.)., College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Justin A
JA
Smith
Department of Physiology and Functional Genomics (A.D.d.K., D.J.P., C.S.), College of Medicine, University of Florida, Gainesville, Florida 32610; Physiology (S.P., J.E.S.), Medical College of Georgia, Augusta University, Augusta, Georgia 30912; and Department of Pharmacodynamics (L.W., H.H., J.A.S., E.G.K.)., College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Colin
C
Sumners
Department of Physiology and Functional Genomics (A.D.d.K., D.J.P., C.S.), College of Medicine, University of Florida, Gainesville, Florida 32610; Physiology (S.P., J.E.S.), Medical College of Georgia, Augusta University, Augusta, Georgia 30912; and Department of Pharmacodynamics (L.W., H.H., J.A.S., E.G.K.)., College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Javier E
JE
Stern
Department of Physiology and Functional Genomics (A.D.d.K., D.J.P., C.S.), College of Medicine, University of Florida, Gainesville, Florida 32610; Physiology (S.P., J.E.S.), Medical College of Georgia, Augusta University, Augusta, Georgia 30912; and Department of Pharmacodynamics (L.W., H.H., J.A.S., E.G.K.)., College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Eric G
EG
Krause
D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism*; D059330:GABAergic Neurons / Q000166:cytology / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology* / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000378:metabolism
D044139:Receptor, Angiotensin, Type 2; C485184:enhanced green fluorescent protein; D001127:Arginine Vasopressin; D049452:Green Fluorescent Proteins