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The Dopamine D 1 Receptor and Angiotensin II Type-2 Receptor are Required for Inhibition of Sodium Transport Through a Protein Phosphatase 2A Pathway

2019; Lippincott Williams & Wilkins; Volume: 73; Issue: 6 Linguagem: Inglês

10.1161/hypertensionaha.119.12705

1524-4563

John J Gildea, Peng Xu, Brandon A. Kemp, Robert M. Carey, Pedro A. José, Robin A. Felder,

Hormonal Regulation and Hypertension

Activation of the renal D 1 R (dopamine D 1 -like receptor) or AT 2 R (angiotensin II type-2 receptor), individually or both, simultaneously, is necessary in the normal regulation of renal sodium (Na + ) transport and blood pressure. However, little is known regarding the precise mechanism of this interaction. Pharmacological stimulation, membrane biotinylation, and cell surface immunofluorescence were used to study the effect of the D 1 R/AT 2 R interaction in human renal proximal tubule cells. D 1 R activation of Gα S stimulates AC (adenylyl cyclase) and induces apical plasma membrane recruitment of AT 2 Rs. We now show for the first time the reciprocal reaction, AT 2 R stimulation with Ang III (angiotensin III) leads to the apical plasma membrane recruitment of the D 1 R. The cell-permeable second messenger analogs of cAMP (8-Br-cAMP) or cGMP (8-Br-cGMP) induce translocation of both D 1 R and AT 2 R to the plasma membrane. Inhibition of PKA (protein kinase A) with Rp-cAMPS and PKG (protein kinase G) with Rp-8-CPT-cGMPS blocks D 1 R and AT 2 R recruitment, respectively, indicating that both PKA and PKG are necessary for D 1 R and AT 2 R trafficking. Both 8-Br-cAMP and 8-Br-cGMP activate PP2A (protein phosphatase 2A), which is necessary for both plasma membrane recruitment of D 1 R and AT 2 R and the inhibition of sodium hydrogen exchanger 3-dependent Na + transport. These studies provide insights into the D 1 R/AT 2 R transregulation mechanisms that play a crucial role in maintaining Na + and ultimately blood pressure homeostasis.