Hypothetical representation of regulation of calcium ion [Ca²⁺]_i homeostasis by PKD-related proteins and summary of potential novel therapeutic interventions targeting major downstream effects of mutations disrupting this pathway. In response to mechanical stimulation of primary cilium, polycystin-1/2 complex mediates Ca²⁺ entry into cell. This triggers Ca²⁺ release from endoplasmic reticulum (ER). Fibrocystin (FC) may regulate [Ca²⁺]_i homeostasis by its interaction with polycystin-2 (PC2) and Ca²⁺-modulating cyclophilin ligand (CAML). Major downstream effects from disruptions of this pathway include elevated cAMP, up-regulated and apically mislocalized epidermal growth factor receptor (EGFR) and up-regulated vasopressin V2 receptor (V2R). Cellular content of cAMP is determined by balance between activities of synthesizing adenylyl cyclases (AC) and catabolizing cAMP phosphodiesterases (PDE). Adenylyl cyclase VI (AC-VI), predominant AC in collecting duct epithelial cells, is stimulated by αs-subunit of heteromeric G proteins (Gs) and is inhibited by Gi and by Ca²⁺. Activation of V2R by vasopressin increases cAMP production. Somatostatin and vasopressin V2 receptor antagonists inhibit cAMP production. PDE1 and PDE4 are predominant PDEs in collecting duct principal cells. PDE1 is activated by Ca²⁺/calmodulin. PKA, Protein kinase A; Src, membrane-associated tyrosine-specific kinase; V2RA, vasopressin 2 receptor antagonist; Src inh, Src inhibitors; EGFRTKI, epidermal growth factor receptor tyrosine kinase inhibitor. Modified from VE Torres and PC Harris: Mechanisms of disease: autosomal dominant and recessive polycystic kidney diseases. Nat Clin Pract Nephrol 2006;2:40-55.