title: Negative feedback from CaSR signaling to aquaporin-2 sensitizes vasopressin to extracellular Ca2.
abstract: We previously described that high luminal Ca(2+) in the renal collecting duct attenuates short-term vasopressin-induced aquaporin-2 (AQP2) trafficking through activation of the Ca(2+)-sensing receptor (CaSR). Here, we evaluated AQP2 phosphorylation and permeability, in both renal HEK-293 cells and in the dissected inner medullary collecting duct, in response to specific activation of CaSR with NPS-R568. In CaSR-transfected cells, CaSR activation drastically reduced the basal levels of AQP2 phosphorylation at S256 (AQP2-pS256), thus having an opposite effect to vasopressin action. When forskolin stimulation was performed in the presence of NPS-R568, the increase in AQP2-pS256 and in the osmotic water permeability were prevented. In the freshly isolated inner mouse medullar collecting duct, stimulation with forskolin in the presence of NPS-R568 prevented the increase in AQP2-pS256 and osmotic water permeability. Our data demonstrate that the activation of CaSR in the collecting duct prevents the cAMP-dependent increase in AQP2-pS256 and water permeability, counteracting the short-term vasopressin response. By extension, our results suggest the attractive concept that CaSR expressed in distinct nephron segments exerts a negative feedback on hormones acting through cAMP, conferring high sensitivity of hormone to extracellular Ca(2+).
authors.affiliation: Dept of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Aldo Moro, 70125, Bari, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Ranieri
authors.affiliation: Dept of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Aldo Moro, 70125, Bari, Italy Istituto Nazionale di Biostrutture e Biosistemi (I.N.B.B.) 00136, Rome, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Tamma
authors.affiliation: Dept of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Aldo Moro, 70125, Bari, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Di Mise
authors.affiliation: Dept of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Aldo Moro, 70125, Bari, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Russo
authors.affiliation: Dept of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Aldo Moro, 70125, Bari, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Centrone
authors.affiliation: Dept of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Aldo Moro, 70125, Bari, Italy Istituto Nazionale di Biostrutture e Biosistemi (I.N.B.B.) 00136, Rome, Italy Centro di Eccellenza di Genomica in campo Biomedico ed Agrario (CEGBA) 70125, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
authors.affiliation: Dept of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Aldo Moro, 70125, Bari, Italy Istituto Nazionale di Biostrutture e Biosistemi (I.N.B.B.) 00136, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Calamita
authors.affiliation: Dept of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Aldo Moro, 70125, Bari, Italy Istituto Nazionale di Biostrutture e Biosistemi (I.N.B.B.) 00136, Rome, Italy Centro di Eccellenza di Genomica in campo Biomedico ed Agrario (CEGBA) 70125, Bari, Italy giovanna.valenti@uniba.it.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Valenti
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009995:Osmosis / Q000187:drug effects; D010627:Phenethylamines; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011437:Propylamines; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D012542:Scattering, Radiation; D015398:Signal Transduction / Q000187:drug effects*; D014667:Vasopressins / Q000494:pharmacology*; D014867:Water / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D051399:Aquaporin 2; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D014867:Water; D014667:Vasopressins; D010768:Phosphoserine; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D002118:Calcium
keywords: AQP2 phosphorylation; Ca2+-sensing receptor; CaSR; Vasopressin