Fig. 11.

Working model of Gpr116 function in A-IC from WT and KO mice. (A) In WT mice, Gpr116 is expressed on the apical membrane of A-ICs. Activation of the receptor leads to an increase in [Ca²⁺]_i and possibly Rho GTPases (48). We hypothesize that Gpr116 acts to decrease surface accumulation of V-ATPase (red arrow) by counteracting the effects of agents, such as aldosterone and adenosine (31, 34), which promote increased surface density of proton pumps. (B) In the absence of Gpr116, there is no counter to the up-regulatory pathways, leading to accumulation of V-ATPase at the apical membrane of A-ICs. This results in increased pumping of protons into the lumen and a decrease to urine pH. By Le Chantelier’s principle, the constant depletion of cytosolic protons causes more CO₂ to diffuse into the cell and combine with H₂O, producing carbonic acid and ultimately more HCO₃⁻ and H⁺, leading to increased HCO₃⁻ reabsorption across the basolateral membrane.