title: Cyclic AMP Recruits a Discrete Intracellular Ca2+Store by Unmasking Hypersensitive IP3Receptors.
abstract: Inositol 1,4,5-trisphosphate (IP3) stimulates Ca2+release from the endoplasmic reticulum (ER), and the response is potentiated by 3',5'-cyclic AMP (cAMP). We investigated this interaction in HEK293 cells using carbachol and parathyroid hormone (PTH) to stimulate formation of IP3and cAMP, respectively. PTH alone had no effect on the cytosolic Ca2+concentration, but it potentiated the Ca2+signals evoked by carbachol. Surprisingly, however, the intracellular Ca2+stores that respond to carbachol alone could be both emptied and refilled without affecting the subsequent response to PTH. We provide evidence that PTH unmasks high-affinity IP3receptors within a discrete Ca2+store. We conclude that Ca2+stores within the ER that dynamically exchange Ca2+with the cytosol maintain a functional independence that allows one store to be released by carbachol and another to be released by carbachol with PTH. Compartmentalization of ER Ca2+stores adds versatility to IP3-evoked Ca2+signals.
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
authors.forename: Vera
authors.initials: V
authors.lastname: Konieczny
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Tovey
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mataragka
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
authors.forename: David L
authors.initials: DL
authors.lastname: Prole
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. Electronic address: cwt1000@cam.ac.uk.
authors.forename: Colin W
authors.initials: CW
authors.lastname: Taylor
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005071:Evoked Potentials / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009116:Muscarine / Q000031:analogs & derivatives / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000819:agonists / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C470184:CLECL1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D037181:Lectins, C-Type; D008565:Membrane Proteins; D010281:Parathyroid Hormone; D034741:RNA, Small Interfering; D043587:Receptor, Muscarinic M3; D044168:Receptor, Parathyroid Hormone, Type 1; C008446:5-methylfurtrethonium; D009116:Muscarine; D002217:Carbachol; D000242:Cyclic AMP; D002118:Calcium
keywords: Golgi apparatus; IRBIT; cyclic AMP; endoplasmic reticulum; inositol 1,4,5-trisphosphate; intracellular Ca(2+) store; parathyroid hormone; phospholipase C