Aquaporin-2 membrane targeting: still a conundrum

The targeting of the water channel aquaporin-2 (AQP2) to the apical plasma membrane of kidney collecting duct principal cells is regulated mainly by the antidiuretic peptide hormone arginine vasopressin (AVP). This process is of crucial importance for the maintenance of body water homeostasis. In this brief review we assess the role of cyclic adenosine monophosphate (cAMP) and discuss the emerging concept that type 2 AVP receptor (V2R)-mediated AQP2 trafficking is cAMP-independent.


the ability of the kidney to concentrate the urine and thereby maintain body water homeostasis depends on targeting of aquaporin-2 (AQP2) to the apical plasma membrane of collecting duct (CD) principal cells (10, 20). This process is mainly regulated by the actions of AVP on the type 2 AVP receptor (V2R), although the V1a receptor may also play a minor role (26). The V2R is classified within the group of 7-transmembrane receptors (7TMR) that bind to the stimulatory guanine nucleotide-binding protein alpha-subunit (Gsα), resulting in activation of adenylyl cyclases (AC) and increased intracellular cAMP.

A role of increased intracellular cAMP levels for modulating AQP2 trafficking has support from a variety of studies. For example, 1) stimulation with the nonspecific AC activator forskolin increases AQP2 membrane accumulation in a mouse cortical collecting duct cell line [e.g., Norregaard et al. (16)]; 2) cAMP increases CD water permeability (15); 3) the cAMP-activated protein kinase A (PKA) can phosphorylate AQP2 on its serine 256 (Ser256) residue in vitro (9), an event that is pivotal for AVP-mediated AQP2 membrane targeting (6, 14); and 4) pharmacological treatment with kinase inhibitor H89 or PKA inhibitor (PKi) prevents V2R-mediated AQP2 plasma membrane accumulation (2, 11). As binding of AVP to the V2R results in increased cAMP levels, this process is generally believed to be the signaling pathway that leads to AQP2 membrane targeting. However, recent studies have brought this widely accepted view of the role of cAMP into question and are the basis for us revisiting this hypothesis here.