Binding of AVP to its receptor on the basolateral membrane activates adenylcyclase, resulting in an increase in intracellular cAMP. This increase in cAMP then activates protein kinase A (PKA), which leads to phosphorylation of AQP2 water channels. Additionally, it results in increased transcription of the AQP2 gene through activation of a cAMP-response element (CRE). The vesicles containing phosphorylated AQP2 are transported towards the apical membrane along microtubules powered by the molecular motor dynein. Once they reach the apical membrane, SNARE proteins facilitate fusion between the vesicles containing AQP2 and the membrane. This fusion allows AQP2 to be added to the membrane, enabling water to enter the cell due to the osmotic gradient. The water then exits the cell across the basolateral membrane through AQP3 and AQP4 water channels that are constantly present in the basolateral membrane. In the absence of AVP occupying the V2 receptor, the AQP2 water channels are removed from the apical membrane via clathrin-mediated endocytosis, making the apical membrane impermeable to water. The endocytosed AQP2 molecules can either be stored in cytoplasmic vesicles for later reinsertion into the apical membrane when plasma AVP levels increase, or they can be degraded. AVP also plays a role in the long-term expression of AQP2 and AQP3. When large volumes of water are ingested over a prolonged period, the abundance of AQP2 and AQP3 in principal cells decreases. Consequently, individuals with psychogenic polydipsia cannot concentrate their urine to the maximum extent when water intake is restricted. Conversely, in conditions of restricted water intake, AQP2 and AQP3 protein expression in principal cells increases, facilitating the excretion of highly concentrated urine. Furthermore, the expression of AQP2 (and sometimes AQP3) varies in pathological conditions that affect urine concentration and dilution. AQP2 expression is reduced in conditions associated with impaired urine concentration, such as hypercalcemia and hypokalemia. On the other hand, conditions characterized by water retention, such as congestive heart failure, hepatic cirrhosis, and pregnancy, lead to an increase in AQP2 expression.
Fig. 35.5 , binding of AVP to its receptor on the basolateral membrane activates adenylcyclase. The increase in intracellular cyclic adenosine monophosphate (cAMP) then activates protein kinase A (PKA), which results in phosphorylation of AQP2 water channels and also results in increased transcription of the AQP2 gene via activation of a cAMP-response element (CRE). Vesicles containing phosphorylated AQP2 move toward the apical membrane along microtubules driven by the molecular motor dynein. Once near the apical membrane, proteins called SNAREs interact with vesicles containing AQP2 and facilitate fusion of these vesicles with the membrane. Addition of AQP2 to the membrane allows water to enter the cell driven by the osmotic gradient (lumen osmolality < cell osmolality). The water then exits the cell across the basolateral membrane through AQP3 and AQP4 water channels, which are constitutively present in the basolateral membrane. When the V2 receptor is not occupied by AVP, the AQP2 water channels are removed from the apical membrane by clathrinmediated endocytosis, thus rendering the apical membrane impermeable to water. The endocytosed AQP2 molecules may be either stored in cytoplasmic vesicles, ready for reinsertion into the apical membrane when AVP levels in the plasma increase, or degraded.
AVP also regulates long-term expression of AQP2 (and AQP3). When large volumes of water are ingested over an extended period of time (e.g., psychogenic polydipsia), the abundance of AQP2 and AQP3 in principal cells is reduced. As a consequence, when water ingestion is restricted, these individuals cannot maximally concentrate their urine. Conversely, in states of restricted water ingestion, AQP2 and AQP3 protein expression in principal cells increases, thereby facilitating excretion of maximally concentrated urine.
It is also clear that expression of AQP2 (and in some instances also AQP3) varies in pathological conditions associated with disturbances in urine concentration and dilution. AQP2 expression is reduced in a number of conditions associated with impaired urine concentrating ability (e.g., hypercalcemia, hypokalemia). By contrast, in conditions associated with water retention (e.g., congestive heart failure, hepatic cirrhosis, pregnancy) AQP2 expression is increased.
CHAPTER 35 Control of Body Fluid Osmolality and Volume 629 • Fig. 35.5 Action of AVP via the V2 receptor on the principal cell of the late distal tubule and collecting duct. See text for details. AC, adenylcyclase; cAMP, cyclic adenosine monophosphate; CREB-P, phosphorylated cAMP response element binding protein; CRE, cAMP response element; P, phosphorylated proteins; AQP2, aquaporin 2; AP2, aquaporin 2 gene. (Adapted from Brown D, Nielsen S. The cell biology of vasopressin action. In: Brenner BM [ed]. The Kidney. 7th ed. Philadelphia: Saunders; 2004.)