D5 dopamine receptor knockout mice and hypertension.
Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. All of the five dopamine receptor genes (D1, D2, D3, D4, and D5) expressed in mammals and some of their regulators are in loci linked to hypertension in humans and in rodents. Under normal conditions, D1-like receptors (D1 and D5) inhibit sodium transport in the kidney and the intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats, and humans with essential hypertension, the D1-like receptor-mediated inhibition of sodium transport is impaired because of an uncoupling of the D1-like receptor from its G protein/effector complex. The uncoupling is genetic, and receptor-, organ-, and nephron segment-specific. In human essential hypertension, the uncoupling of the D1 receptor from its G protein/effector complex is caused by an agonist-independent serine phosphorylation/desensitization by constitutively active variants of the G protein-coupled receptor kinase type 4. The D5 receptor is also important in blood pressure regulation. Disruption of the D5 or the D1 receptor gene in mice increases blood pressure. However, unlike the D1 receptor, the hypertension in D5 receptor null mice is caused by increased activity of the sympathetic nervous system, apparently due to activation of oxytocin, V1 vasopressin, and non-N-methyl D-aspartate receptors in the central nervous system. The cause of the activation of these receptors remains to be determined.
Yang
Zhiwei
Z
Georgetown University Medical Center, Washington, District of Columbia, USA. zy4@georgetown.edu
Sibley
David R
DR
Jose
Pedro A
PA
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D017447:Receptors, Dopamine D1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D050641:Receptors, Dopamine D5; D011963:Receptors, GABA-A / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology; D018045:Receptors, Oxytocin / Q000502:physiology; D017483:Receptors, Vasopressin / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology
C493606:Drd5 protein, mouse; D017447:Receptors, Dopamine D1; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D050641:Receptors, Dopamine D5