Aquaporin-2 in the "-omics" era

Abstract

Vasopressin controls renal water excretion largely through actions to regulate the water channel aquaporin-2 in collecting duct principal cells. Our knowledge of the mechanisms involved has increased markedly in recent years with the advent of methods for large-scale systems-level profiling such as protein mass spectrometry, yeast two-hybrid analysis, and oligonucleotide microarrays. Here we review this progress.

FIGURE 1.

AVP signaling pathways in the renal IMCD. Occupation of the V2R by AVP (right) triggers signaling mechanisms that result in at least three downstream effects vital to AQP2 trafficking (yellow boxes on left). Adenylyl cyclases III (AC III) and VI (AC VI) produce cAMP, most of whose effects are mediated by PKA, including phosphorylation of AQP2 at Ser²⁵⁶, followed by downstream phosphorylation at Ser²⁶⁴ and Ser²⁶⁹ (top). These phosphorylation events alter binding interactions with regulatory proteins (see text). In addition, RhoA is inactivated, possibly due to PKA-mediated phosphorylation of RhoA (center) and leading to F-actin depolymerization. AVP also triggers spike-like increases in intracellular calcium due to either phosphorylation of RyR1 or Epac (RapGEF3) effects. Calcium mobilization causes calmodulin (CaM)-ependent phosphorylation of the MRLC (MLC) by MLCK, resulting in non-muscle myosin II activation and long-distance translocation of AQP2 vesicles to the apical region.

FIGURE 2.

C-terminal tail of AQP2. Shown are the C-terminal 51 amino acids of rat AQP2, demonstrating relevant post-translational modifications and binding interactions. Binding interactions for actin and hsp70 are favored by lack of phosphorylation at Ser²⁵⁶ (NP), whereas binding interactions for tropomyosin 5b and BiP are favored by the presence of phosphorylation at Ser²⁵⁶ (P).