Basic Pharmacology Of Vasopressin

VASOPRESSIN RECEPTORS The cellular effects of vasopressin are mediated mainly by its interactions with the 3 types of receptors, Vla Vlb, and V2. The Vla receptor is the most widespread subtype of vasopressin receptor; it is found in vascular smooth muscle, the adrenal gland, myometrium, the bladder, adipocytes, hepatocytes, platelets, renal medullary interstitial cells, vasa recta in the renal microcirculation, epithelial cells in the renal cortical collecting-duct, spleen, testis, and many CNS structures. V1b receptors have a more Limited distribution and are found in the anterior pituitary, several brain regions, the pancreas, and the adrenal medulla. V2 receptors are located predominantly in principal cells of the renal collecting-duct system but also are present on epithelial cells in the thick ascending limb and on vascular endothelial cells. Vasopressin receptors are GPCRs.


Figure 29-2 summarizes the current model of V] receptor-effector coupling. Vasopressin binding to V] receptors activates the G—PLC pathway, ultimately causing biological effects that include immediate responses (e.g., vasoconstriction, glycogenolysis, platelet aggregation, and ACTH release) and growth of smooth muscle cells.


Principal cells in the renal collecting duct have V2 receptors on their basolateral membranes that couple to Gs to stimulate adenylyl cyclase activity (Figure 29-3). The resulting increase in cellular cyclic AMP and PKA activity triggers increased insertion of water channel-containing vesicles (WCVs) into the apical membrane and decreased endocytosis of WCVs from the apical membrane. The distribution of WCVs between the cytosolic compartment and the apical membrane compartment thus is shifted in favor of the apical membrane compartment. Because WCVs contain preformed aquaporin 2 water channels, their net shift into apical membranes in response to V2-receptor stimulation greatly increases water permeability of the apical membrane.

Aquaporins are a family of water channel proteins that allow water molecules to cross biological membranes. Of the ]0 cloned mammalian aquaporins, at least 7 are found in the kidney. Aquaporin ] is present in the apical and basolateral membrane of the proximal tubule and in the thin descending limb. Aquaporin 2 resides in the apical membrane and WCVs of the collecting-duct principal cells, whereas aquaporins 3 and 4 are present in the basolateral membrane of principal cells. Aquaporin 7 is in the apical brush border of the straight proximal tubule. Aquaporins 6 and 8 are

Types Networks

Vasoconstriction Glycogenosis Platelet aggregation ACTH Release

Immediate Cell responses growth

FIGURE 29-2 Mechanism of V1 receptor—effector coupling. Binding of 8-arginine vasopressin (AVP) to V1 vasopressin receptors (V1) stimulates several membrane-bound phospholipases. Stimulation of the G^-PLC^ pathway results in IP3 formation, mobilization of intracellular Ca2+, and activation of PKC. Activation of V1 receptors also causes influx of extracellular Ca2+ by an unknown mechanism. PKC and Ca2+/calmodulin-activated protein kinases phospho-rylate cell-type-specific proteins leading to cellular responses. A further component of the AVP response derives from the production of eicosanoids secondary to the activation of PLA^ the resulting mobilization of arachidonic acid (AA) provides substrate for eicosanoid synthesis via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, leading to local production of prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT), which may activate a variety of signaling pathways, including those linked to GS and Gq. Biological effects mediated by the V1 receptor include vasoconstriction, glycogenolysis, platelet aggregation, ACTH release, and growth of vascular smooth muscle cells. The effects of vasopressin on cell growth involve transcriptional regulation via the FOS/JUN AP-1 transcription complex.

located intracellularly in the collecting-duct principal cells. In addition to increasing the insertion of aquaporin 2 into apical membranes in collecting-duct principal cells, vasopressin also increases the expression of aquaporin 2 mRNA and protein. Chronic dehydration leads to long-term up-regulation of aquaporin 2 and water transport in the collecting duct.

For maximum concentration of urine, large amounts of urea must be deposited in the intersti-tium of the inner medullary collecting duct. It is not surprising, therefore, that V2-receptor activation also increases urea permeability by 400% in the terminal portions of the inner medullary collecting duct by activating a vasopressin-regulated urea transporter (termed VRUT, UT1, or UT-A1), most likely by PKA-induced phosphorylation. The kinetics of vasopressin-induced water and urea permeability differ, and vasopressin-induced regulation of VRUT does not entail vesicular trafficking to the plasma membrane.

In addition to increasing the water permeability of the collecting duct and the urea permeability of the inner medullary collecting duct, V2-receptor activation also increases Na+ transport in the thick ascending limb and collecting duct. Increased Na+ transport in the thick ascending limb is mediated by three mechanisms that affect the Na+—K+—2C1~ symporter: rapid phosphorylation of the symporter, translocation of the symporter into the luminal membrane, and increased

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