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

Activation of the renal DR (dopamine D-like receptor) or ATR (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 DR/ATR interaction in human renal proximal tubule cells. DR activation of Gα stimulates AC (adenylyl cyclase) and induces apical plasma membrane recruitment of ATRs. We now show for the first time the reciprocal reaction, ATR stimulation with Ang III (angiotensin III) leads to the apical plasma membrane recruitment of the DR. The cell-permeable second messenger analogs of cAMP (8-Br-cAMP) or cGMP (8-Br-cGMP) induce translocation of both DR and ATR to the plasma membrane. Inhibition of PKA (protein kinase A) with Rp-cAMPS and PKG (protein kinase G) with Rp-8-CPT-cGMPS blocks DR and ATR recruitment, respectively, indicating that both PKA and PKG are necessary for DR and ATR trafficking. Both 8-Br-cAMP and 8-Br-cGMP activate PP2A (protein phosphatase 2A), which is necessary for both plasma membrane recruitment of DR and ATR and the inhibition of sodium hydrogen exchanger 3-dependent Na transport. These studies provide insights into the DR/ATR transregulation mechanisms that play a crucial role in maintaining Na and ultimately blood pressure homeostasis.