Vasopressin and vasopressin receptors

vasopressin

Vasopressin (VP, antidiuretic hormone (ADH), arginine vasopressin (AVP)) is a small nine-amino acid peptide, which acts both as hormone and neurotransmitter (or neuromodulator). Arginine vasopressin is the form found in humans and most mammals; lysine vasopressin (lypressin), found for example in pigs, has lysine in place of the arginine as the eighth amino acid. Oxytocin is structurally very similar to vasopressin, and differs only by two amino acids, leading to some cross-reactions.

Vasopressin pre-prohormone is produced mainly in the hypothalamus, from where it is transported to the posterior pituitary gland for storage and release. The pre-prohormone protein is cleaved during its way in pituitary stalk to vasopressin, neurophysin II, and copeptin, which are released in the blood simultaneously in equimolar amounts. Some vasopressin is also transported to the anterior pituitary, to stimulate production of adrenocorticotrophic (ACTH). Half-life of vasopressin is ∼3 min. Vasopressin is metabolized in the liver and kidneys, but mostly excreted in urine, where its concentration is much higher than in blood.

Physiological concentrations of vasopressin in plasma (0-3 pM) are difficult to measure reliably, but measurement of more stable copeptin is a good surrogate marker of vasopressin.

Hypothalamus monitors the osmolality of the plasma, and responds to increased osmolality by stimulating the secretion of vasopressin. Relationship between vasopressin secretion and plasma osmolality has individual variation with strong heritability. In addition to plasma osmolality, vasopressin secretion is stimulated by a decrease in (arterial) blood volume, and anticipatory signals (for instance to drinking) and stress.

Vasopressin receptors

Vasopressin has three G-protein coupled receptors (GPCRs), AVPR1A, AVPR1B (AVPR3), and AVPR2 (or V1aR, V1bR, and V2R). Binding to AVPR1s activates Ca2+ pathway and binding to AVPR2 activates cAMP pathway. AVPR1As and AVPR1Bs are expressed in the nervous system, but AVPR2 is not, which has led to development of AVPR1-specific compounds to be used as CNS drugs (Fabio et al., 2012).

Arginine vasopressin receptor 1A (AVPR1A)

AVPR1A is expressed in the brain, the liver, the kidneys, adrenal glands, and in smooth muscle cells in peripheral vasculature. In the brain, the highest levels of AVPR1A are found in the cerebral cortex, limbic system, hypothalamus, and brainstem. AVPR1As are also present in the spinal cord, including locations of sympathetic pregangliotic neurons, supporting their role in modulation of autonomic control of blood pressure.

Polymorphisms of AVPR1A gene are associated to differences in traits such as partner bonding, novelty seeking and harm avoidance, and social interaction skills. Blocking of AVPR1A may improve social communication in autism spectrum disorder.

In the kidneys, AVPR1A is expressed on the luminal side of collecting ducts, exposed to urinary vasopressin, and in interstitial cells of the medulla. Activation leads to production of prostaglandins, which increase medullary blood flow via vasodilation.

In the liver, vasopressin (like glucagon) stimulates many metabolic pathways, including glycogenolysis, gluconeogenesis, and ureagenesis.

SRX246 is a selective AVPR1A antagonist, that could be labelled with positron-emitting radionuclides (Fabio et al., 2012). Imaging studies with these radiotracers have not been reported, but another antagonist has provided promising results in mice studies; however, AVPR1A binding in the brain is very dependent on the anaesthetic (Naik et al., 2017).

Arginine vasopressin receptor 1B (AVPR1B)

AVPR1B is expressed in the anterior pituitary, and in the brain, although less widespread than AVPR1A. Central AVPR1Bs have a role in the stress responses, especially in the adaptation to stress, and in social motivation, aggression, anxiety, depression, and memory. AVPR1Bs are also expressed in pancreatic islets, where vasopressin stimulates the secretion of either insulin by β-cells or glucagon by α-cells, depending on the blood glucose level.

AVPR1B antagonist SSR145419 has been labelled with 11C, but brain uptake in the primate study was low, expect in the pituitary (Schönberger et al., 2010).

Arginine vasopressin receptor 2 (AVPR2)

AVPR2 is expressed in the kidneys and in endothelial cells of the vasculature. Activated AVPR2 with vasopressin is internalized and enters lysosomal degradation compartment, but continues cAMP signalling for some time. Resensitization to vasopressin requires synthesis of new AVPR2.

In the kidneys, AVPR2 is found predominantly in the membranes of distal convoluted tubules and collecting ducts. Activation of AVPR2 leads to increased [cAMP], and further to phosphorylation of several proteins, including aquaporin AQP2. Phosphorylated AQP2 accumulates in the apical plasma membrane of principal cells of the collecting ducts, increasing water permeability, which facilitates the osmotically driven reabsorption of water (antidiuretic effect). Lack of vasopressin leads to very high (>10 L/day) urine production (diabetes insipidus). Major proportion of water and sodium reabsorption happens before water reaches the collecting ducts, and is kept steady with renal autoregulation; the minor proportion of reabsorption that takes place in collecting ducts is heavily regulated with vasopressin.

AVPR2s in vascular endothelium induce vasodilation via production of NO.

1-desamino-8-D-arginine vasopressin (DDAVP) is a specific agonist for AVPR2. Tolvaptan is a specific antagonist for AVPR2


See also:



References:

Bankir L, Bichet DG, Morgenthaler NG. Vasopressin: physiology, assessment and osmosensation. J Intern Med. 2017; 282: 284-297. doi: 10.1111/joim.12645.

Lozić M, Šarenac O, Murphy D, Japundźić-Žigon N. Vasopressin, central autonomic control and blood pressure regulation. Curr Hypertens Rep. 2018; 20(2):11. doi: 10.1007/s11906-018-0811-0.

Skorecki K, Chertow GM, Marsden PA, Taal MW, Yu ASL, Wasser WG. Brenner & Rector’s The Kidney. 10th ed. Elsevier, 2016. ISBN: 978-1-4557-4836-5.

Yang B (ed.): Aquaporins. Springer, 2017. doi: 10.1007/978-94-024-1057-0.



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Created at: 2018-07-07
Updated at: 2018-08-21
Written by: Vesa Oikonen