Vasopressin and disruption of calcium signalling in polycystic kidney disease

Polycystin-1 and polycystin-2 in the primary cilia and endoplasmic reticulum regulate intracellular calcium signalling; mutations in these proteins cause autosomal dominant polycystic kidney disease (ADPKD)In ADPKD, reduced intracellular calcium increases the generation of and inhibits the destruction of cAMP, and reduces the release of ATPAltered cAMP metabolism and purinergic signalling in collecting duct principal cells and distal nephron epithelial cells markedly increases the sensitivity of these cells to the constant tonic effects of vasopressinIncreased protein kinase A activity leads to phosphorylation of polycystin-2, ryanodine receptors and inositol 1,4,5-trisphosphate receptors, increasing leakage of calcium from the endoplasmic reticulum, which further disrupts intracellular calcium signallingThe reduction in intracellular calcium that results from mutant polycystin-1 or polycystin-2 causes the cellular response to cAMP to switch from suppression to stimulation of proliferationIn vivo studies support the hypothesis that disruption of intracellular calcium signalling has a central role in the pathogenesis of ADPKD