The Biology of Vasopressin

Abstract

Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin synthesis in several cell types, storage in intracellular vesicles, and release in response to physiological stimuli are highly regulated and mediated by three distinct G protein coupled receptors. Other receptors may bind or cross-bind vasopressin. Vasopressin is regulated spatially and temporally through transcriptional and post-transcriptional mechanisms, sex, tissue, and cell-specific receptor expression. Anomalies of vasopressin signaling have been observed in polycystic kidney disease, chronic heart failure, and neuropsychiatric conditions. Growing knowledge of the central biological roles of vasopressin has enabled pharmacological advances to treat these conditions by targeting defective systemic or central pathways utilizing specific agonists and antagonists.

Keywords: GPCRs; cardiac function; renal function; sex differences; social behavior; vasopressin.

Figure 1

AVP (arginine vasopressin) synthesis and structure. (A) The hypothalamic neurosecretory neurons synthesize the pre-pro-hormone precursor called pre-pro-AVP or AVP-neurophysin-copeptin. The signal peptide is cleaved by a signalase in the endoplasmic reticulum to form pro-pressinphysin. Copeptin is glycosylated and cleaved by an endopeptidase in the Golgi [8,35,45]. Such endopeptidase also separates the pro-AVP vasopressinyl-Gly-Lys-Arg peptide from neurophysin, and pro-AVP is enclosed in vesicles. The C-terminal arginine and lysine are trimmed by carboxypeptidase E and the newly exposed C-terminal glycine is oxidized by glycine monooxygenase into hydroxyl-glycine. Finally, a lyase converts hydroxyl-glycine is into an amide group which subsequently reacts with glyoxylic acid to yield AVP [45]. (B) AVP structure. Note the cyclic structure and primary amide (NH₂).

Figure 2

Intracellular response to AVP in renal tubular epithelial cells. AVP binds to the V2R G-protein coupled receptor on the basolateral membrane, which activates adenylyl-cyclase (AC). Produced cAMP activates protein kinase A (PKA), which phosphorylates the AQP2 water channels stored in vesicular compartments. This promotes apical membrane relocation and increased transmembrane water transport (modified after [95]).

Figure 3

V2R and AVP signaling in normal and autosomal dominant polycystic kidney disease (ADPKD) renal tubule epithelial cells. In normal cells, AVP binding to V2R promotes dissociation of the trimeric G_s into its α and βγ subunits. The α subunit triggers adenylyl cyclase (AC)-mediated cAMP synthesis, which activates PKA and phosphorylates AQP2. Phospho-AQP2 is shuttled to the apical cell membrane and water reabsorption increased. In ADPKD (red type), reduced Ca²⁺ release from the ER and impaired Ca²⁺ import from polycystin 2 at the primary cilia elevate intracellular cAMP (dashed), which in turn increases fluid excretion. Resulting dehydration triggers AVP release from the pituitary. Furthermore, higher than normal intracellular cAMP in ADPKD boosts Cl⁻ transport via the cystic fibrosis transmembrane conductance regulator (CFTR) channel that contributes to cystic cell proliferation and chloride-dependent fluid secretion.

Figure 4

AVP-V1aR signaling contributes to weaker myocardial contractions and cardiac remodeling in heart failure (HF). (A) AVP binding to V1aR during HF activates G_αq protein-mediated signaling, which amplifies IP₃ signaling and triggers Ca²⁺ release (dashed) from the sarcoplasmic reticulum (SR). Prolonged Ca²⁺ mobilization leads to myocardial hypertrophy. (B) G_αq-independent signaling promotes GRK recruitment to the plasma membrane (PM) decreasing catecholamine-β adrenergic receptor (βAR) activation and Ca²⁺ mobilization. When prolonged, this condition impairs myocardial contractions.