title: Role of 1,2-sn diacylglycerol in airway smooth muscle stimulated by carbachol.
abstract: Activation of muscarinic receptors in airway smooth muscle leads to breakdown of membrane polyphosphoinositides. In agreement with others, we show here that muscarinic stimulation elicits inositol-1,4,5-triphosphate formation. In addition, we show that carbachol also elicits total diacylglycerol and 1,2-sn diacylglycerol accumulation in a specific and dose-dependent manner (EC50 values: 2.1 x 10(-8) M for 1,2-sn diacylglycerol). The time-course of inositol-1,4,5-triphosphate accumulation is compatible with that of the clonic phase of muscle contraction. Since this derivative can mobilize intracellular Ca2+ stores, it may play a second-messenger role in the initial phase of contraction. The time-course of diacylglycerol accumulation is compatible with the muscarinic-induced tonic phase of smooth-muscle contraction. Carbachol induces similar dose-dependent reductions in isoproterenol-induced muscle relaxation (EC50 values for relaxation concentration-response curves to isoproterenol: 3 x 10(-6) M and 2.1 x 10(-5) M, with carbachol at 10(-7) M and 10(-4) M, respectively), and increases in adenylate cyclase activity (EC50 values for the concentration-response to isoproterenol: 1.2 x 10(-6) M and 1.5 x 10(-5) M, with carbachol at 10(-7) M and 10(-4) M, respectively). Since it is known that carbachol-induced uncoupling of beta 2-adrenergic receptors is proportional to the breakdown of polyphosphoinositides, and that 1,2-sn diacylglycerol is a potent activator of protein kinase C, 1,2-sn diacylglycerol could be mediating the uncoupling of beta 2-adrenergic receptors, via activation of alpha-protein kinase C and subsequent phosphorylation of receptor, and/or cyclase, and/or G proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Département de Pneumologie et de Physiologie Respiratoire, Hôpital Universitaire Cochin, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Roux
authors.forename: E
authors.initials: E
authors.lastname: Mavoungou
authors.forename: E
authors.initials: E
authors.lastname: Naline
authors.forename: H
authors.initials: H
authors.lastname: Lacroix
authors.forename: C
authors.initials: C
authors.lastname: Tordet
authors.forename: C
authors.initials: C
authors.lastname: Advenier
authors.forename: B M
authors.initials: BM
authors.lastname: Grandordy
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D002417:Cattle; D004075:Diglycerides / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology; D013268:Stimulation, Chemical; D013997:Time Factors; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D000262:Adenylyl Cyclases; D007545:Isoproterenol