# Vasopressin receptor

The actions of vasopressin are mediated by stimulation of tissue-specific G protein-coupled receptors (GPCRs) called vasopressin receptors that are classified into the V$_1$ (V$_{1A}$), V$_2$, and V$_3$ (V$_{1B}$) receptor subtypes. These three subtypes differ in localization, function and signal transduction mechanisms.

## Subtypes

There are three subtypes of vasopressin receptor: V$_{1A}$ (V$_1$), V$_{1B}$ (V$_3$) and V$_2$.
| Subtype (symbol) | Subtype (symbol) | Subtype (symbol) | Signaling pathways | Location | Function |
| gene | receptor | receptor | | Signaling pathways | Location | Function |
| gene | IUPHAR | alternate | Signaling pathways | Location | Function |
| AVPR1A | V$_{1A}$ | V$_1$ | G protein-coupled, phosphatidylinositol/calcium | vascular smooth muscle, platelet, hepatocytes, myometrium | vasoconstriction, myocardial hypertrophy, platelet aggregation, glycogenolysis, uterine contraction |
| AVPR1B | V$_{1B}$ | V$_3$ | G protein-coupled, phosphatidylinositol/calcium | anterior pituitary gland | releases ACTH, prolactin, endorphins |
| AVPR2 | V$_2$ | V$_2$ | Adenylyl cyclase/cAMP | basolateral membrane of collecting duct, vascular endothelium and vascular smooth muscle cell | insertion of AQP-2 water channels into apical membrane, induction of AQP-2 synthesis, releases von Willebrand factor and factor VIII, vasodilation |

### V$_1$ receptor

V$_1$ receptors (V$_1$Rs) are found in high density on vascular smooth muscle and cause vasoconstriction by an increase in intracellular calcium via the phosphatidyl–inositol-bisphosphate cascade. Cardiac myocytes also possess V$_1$R. Additionally V$_1$R are located in brain, testis, superior cervical ganglion, liver, blood vessels, and renal medulla.
V$_1$R is present on platelets, which upon stimulation induces an increase in intracellular calcium, facilitating thrombosis. Studies have indicated that due to polymorphism of platelet V$_1$R there is significant heterogeneity in the aggregation response of normal human platelets to vasopressin.
V$_1$Rs are found in kidney, where they occur in high density on medullary interstitial cells, vasa recta, and epithelial cells of the collecting duct. Vasopressin acts on medullary vasculature through V$_1$R to reduce blood flow to inner medulla without affecting blood flow to outer medulla. V$_1$Rs on the luminal membrane of the collecting duct limit the antidiuretic action of vasopressin. Additionally, vasopressin selectively contracts efferent arterioles probably through the V$_1$R, but not the afferent arteriole.

### V$_2$ receptor

V$_2$ receptor (V$_2$R) differs from V$_1$R primarily in the number of sites susceptible to N-linked glycosylation; the V$_1$R has sites at both the amino-terminus and at the extracellular loop, whereas the V$_2$R has a single site at the extracellular amino-terminus.
The well known antidiuretic effect of vasopressin occurs via activation of V$_2$R. Vasopressin regulates water excretion from the kidney by increasing the osmotic water permeability of the renal collecting duct – an effect that is explained by coupling of the V$_2$R with the G$_s$ signaling pathway, which activates cAMP. The V$_2$R continues to activate G$_s$ after being internalized by β-arrestin rather than being desensitized. This internalized G$_s$ signaling by V$_2$R is explained by the receptors ability to form "mega-complexes" consisting of a single V$_2$R, β-arrestin, and heterotrimeric G$_s$. The increased intracellular cAMP in the kidney in turn triggers fusion of aquaporin-2-bearing vesicles with the apical plasma membrane of the collecting duct principal cells, increasing water reabsorption.

### V$_3$ receptor

The human V$_3$ receptor (V$_3$R, previously known as V$_{1B}$R) is a G-protein-coupled pituitary receptor that, because of its scarcity, was only recently characterized. The 424-amino-acid sequence of the V$_3$R has homologies of 45%, 39%, and 45% with the V$_1$R, V$_2$R and oxytocin receptor (OTR), respectively. However, V$_3$R has a pharmacologic profile that distinguishes it from the human V$_1$R and activates several signaling pathways via different G-proteins, depending on the level of receptor expression.

## Function

Although all three of these proteins are G-protein coupled receptors (GPCRs), activation of AVPR1A and AVPR1B stimulate phospholipase C, while activation of AVPR2 stimulates adenylate cyclase. These three receptors for vasopressin have unique tissue distributions. AVPR1A are expressed in vascular smooth muscle cells, hepatocytes, platelets, brain cells, and uterus cells. AVPR1B are expressed in cells of the anterior pituitary and throughout the brain, especially in the pyramidal neurons of the hippocampal CA2 field. AVPR2 are expressed in the kidney tubule, predominantly in the distal convoluted tubule and collecting ducts, in fetal lung tissue and lung cancer, the last two being associated with alternative splicing. AVPR2 is also expressed in the liver where stimulation releases a variety of clotting factors into the bloodstream. In the kidney, AVPR2's primary function is to respond to arginine vasopressin by stimulating mechanisms that concentrate the urine and maintain water homeostasis in the organism. When the function of AVPR2 is lost, the disease Nephrogenic Diabetes Insipidus (NDI) results.

## Antagonists

Vasopressin receptor antagonists (VRAs) are drugs that block vasopressin receptors. Most commonly VRAs are used to treat hyponatremia caused by syndrome of inappropriate antidiuretic hormone secretion (SIADH), congestive heart failure (CHF) and cirrhosis.
Somatostatin is a competitive inhibitor.
Normally, when osmolality falls below its set point, plasma vasopressin levels become undetectable, and an aquaresis results. In SIADH, vasopressin release is not fully suppressed, despite hypotonicity. In cirrhosis and CHF, impaired delivery of solute to the diluting sites or diminished glomerular filtration rate causes impairment of maximal water-excretory capacity, resulting in persistence of vasopressin release leading to water retention.
Vasopressin receptor antagonists include the new class of "vaptan drugs" such as conivaptan, tolvaptan, mozavaptan, lixivaptan, satavaptan etc.