Minireview: Aquaporin 2 Trafficking

Abstract

In the kidney aquaporin-2 (AQP2) provides a target for hormonal regulation of water transport by vasopressin. Short-term control of water permeability occurs via vesicular trafficking of AQP2 and long-term control through changes in the abundance of AQP2 and AQP3 water channels. Defective AQP2 trafficking causes nephrogenic diabetes insipidus, a condition characterized by the kidney inability to produce concentrated urine because of the insensitivity of the distal nephron to vasopressin. AQP2 is redistributed to the apical membrane of collecting duct cells through activation of a cAMP signaling cascade initiated by the binding of vasopressin to its V2-receptor. Protein kinase A-mediated phosphorylation of AQP2 has been proposed to be essential in regulating AQP2-containing vesicle exocytosis. Cessation of the stimulus is followed by endocytosis of the AQP2 proteins exposed on the plasma membrane and their recycling to the original stores, in which they are retained. Soluble N-ethylmaleimide sensitive fusion factor attachment protein receptors (SNARE) and actin cytoskeleton organization regulated by small GTPase of the Rho family were also proved to be essential for AQP2 trafficking. Data for functional involvement of the SNARE vesicle-associated membrane protein 2 in AQP2 targeting has recently been provided. Changes in AQP2 expression/trafficking are of particular importance in pathological conditions characterized by both dilutional and concentrating defects. One of these conditions, hypercalciuria, has shown to be associated with alteration of AQP2 urinary excretion. More precisely, recent data support the hypothesis that, in vivo external calcium, through activation of calcium-sensing receptors, modulates the expression/trafficking of AQP2. Together these findings underscore the importance of AQP2 in kidney pathophysiology.

Acute Hypertonicity Alters Aquaporin-2 Trafficking and Induces a MAPK-dependent Accumulation at the Plasma Membrane of Renal Epithelial Cells

“…A large body of work has focused on mechanisms that govern accumulation of AQP2 at the cell surface in response to VP (9,11,13). This is the first study to directly address the effects of hypertonicity on AQP2 trafficking during the first minutes of hypertonic stimulation.…”

“…Since the PKA consensus sequence (RRQS 256 in AQP2) is not an MAPK target, MAPK activation could enhance PKA-mediated phosphorylation of AQP2. Alternatively, modulated activity of proteins involved in AQP2 shuttling (11,13,56), such as SNAP, SNARE, and endocytotic adaptors, may be targeted by hypertonicity-induced signaling pathways. Finally, cytoskeleton remodeling plays a major role in AQP2 trafficking (13), and modulation of the cytoskeleton by hypertonicity may represent another means by which AQP2 cell surface accumulation is achieved.…”

“…In addition to VP, other factors modulate AQP2 expression at the cell surface. These include dopamine, prostaglandin E 2 , and agents that increase cGMP concentration (11)(12)(13).…”

An emerging consensus on aquaporin translocation as a regulatory mechanism

“…Subsequently, the G protein, Gs, initiates adenylate cyclase activation leading to increases in cyclic AMP which mediates activation of protein kinase A (PKA) and results in phosphorylation of serine 256 on the C-terminus of AQP2. This facilitates AQP2 translocation to the plasma membrane and water reabsorption in order to maintain osmotic homeostasis (see (Valenti et al, 2005) for review).…”

Glutathionylation of the Aquaporin-2 Water Channel

“…The aquaporins (AQPs) 2 are a family of integral membrane proteins that mediate water transport across membranes in response to osmotic gradients. In the kidney, AQP2 is the most characterized aquaporin controlling renal collecting duct water balance, being a selective target of the hormone vasopressin.…”