Schematic representation of the effect of arginine vasopressin (AVP) to increase water permeability in the principal cells of the collecting duct. AVP is bound to the V2 receptor (a G-protein-linked receptor) on the basolateral membrane. The basic process of G-protein-coupled receptor signaling consists of three steps: a hepta-helical receptor that detects a ligand (in this case, AVP) in the extracellular milieu, a G-protein that dissociates into an alpha subunit bound to GTP and beta and gamma subunits after interaction with the ligand-bound receptor, and an effector (in this case, adenylyl cyclase) that interacts with dissociated G-protein subunits to generate small-molecule second messengers. AVP activates adenylyl cyclase increasing the intracellular concentration of cyclic adenosine monophosphate (cAMP). The topology of adenylyl cyclase is characterized by two tandem repeats of six hydrophobic transmembrane domains separated by a large cytoplasmic loop and terminates in a large intracellular tail. Generation of cAMP follows receptor-linked activation of the heteromeric G-protein (Gs) and interaction of the free Gαs-chain with the adenylyl cyclase catalyst. Protein kinase A (PKA) and possibly the exchange factor directly activated by cAMP (EPAC) are the target of the generated cAMP. In the long term, vasopressin also increases aquaporin-2 (AQP2) expression via phosphorylation of the cAMP responsive element binding protein (CREB), which stimulates transcription from the AQP2 promoter. Cytoplasmic vesicles carrying the water channel proteins (represented as homotetrameric complexes) are fused to the luminal membrane in response to AVP, thereby increasing the water permeability of this membrane. Microtubules and actin filaments are necessary for vesicle movement toward the membrane. The mechanisms underlying docking and fusion of AQP2-bearing vesicles are not known. The detection of the small GTP-binding protein Rab3a, synaptobrevin 2 and syntaxin 4 in principal cells suggests that these proteins are involved in AQP2 trafficking [20]. When AVP is not available, water channels are retrieved by an endocytic process, and water permeability returns to its original low rate. Internalized AQP2 can either be targeted to recycling pathways or to degradation via lysosomes. AQP3 and AQP4 water channels are expressed on the basolateral membrane. The importance of an endoplasmic reticulum calcium sensor for vasopressin/aquaporin signaling is also represented with coupling between STIM1 and Orai1 during calcium depletion possibly induced by AQP2 signaling [17].