title: Cyclic AMP directs inositol (1,4,5)-trisphosphate-evoked Ca2+ signalling to different intracellular Ca2+ stores.
abstract: Cholesterol depletion reversibly abolishes carbachol-evoked Ca(2+) release from inositol (1,4,5)-trisphosphate (IP3)-sensitive stores, without affecting the distribution of IP3 receptors (IP3R) or endoplasmic reticulum, IP3 formation or responses to photolysis of caged IP3. Receptors that stimulate cAMP formation do not alone evoke Ca(2+) signals, but they potentiate those evoked by carbachol. We show that these potentiated signals are entirely unaffected by cholesterol depletion and that, within individual cells, different IP3-sensitive Ca(2+) stores are released by carbachol alone and by carbachol combined with receptors that stimulate cAMP formation. We suggest that muscarinic acetylcholine receptors in lipid rafts deliver IP3 at high concentration to associated IP3R, stimulating them to release Ca(2+). Muscarinic receptors outside rafts are less closely associated with IP3R and provide insufficient local IP3 to activate IP3R directly. These IP3R, probably type 2 IP3R within a discrete Ca(2+) store, are activated only when their sensitivity is increased by cAMP. Sensitization of IP3R by cAMP extends the effective range of signalling by phospholipase C, allowing muscarinic receptors that are otherwise ineffective to recruit additional IP3-sensitive Ca(2+) stores.
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.forename: Colin W
authors.initials: CW
authors.lastname: Taylor
mesh_terms: D016723:Bone Remodeling; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002217:Carbachol / Q000378:metabolism; D002784:Cholesterol; D000242:Cyclic AMP / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000031:analogs & derivatives; D020239:Receptor Cross-Talk; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; C473449:PTH1R protein, human; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D011976:Receptors, Muscarinic; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D002784:Cholesterol; D000242:Cyclic AMP; D010738:Type C Phospholipases; D002118:Calcium
keywords: Calcium signalling; Cholesterol; Cyclic AMP; IP3 receptor; Spatial organization