title: Nicotine-induced phosphorylation of extracellular signal-regulated protein kinase and CREB in PC12h cells.
abstract: We have investigated mechanisms of nicotine-induced phosphorylation of extracellular signal-regulated protein kinase (p42/44 MAP kinase, ERK) and cAMP response element binding protein (CREB) in PC12h cells. Nicotine transiently induced ERK phosphorylation at more than 1 microM. The maximal level of nicotine-induced ERK phosphorylation was lower than that of the membrane depolarization induced and, to a great extent, the nerve growth factor (NGF)-induced ERK phosphorylation. Nicotinic acetylcholine receptor (nAChR) alpha7 subunit-selective inhibitors had no significant effect on nicotine-induced ERK phosphorylation. L-Type voltage-sensitive calcium channel antagonists inhibited nicotine-induced ERK phosphorylation. Calcium imaging experiments showed that alpha7-containing nAChR subtypes were functional at 1 microM of nicotine in the nicotine-induced calcium influx, and non-alpha7 nAChRs were prominent in the Ca(2+) influx at 50 microM of nicotine. An expression of dominant inhibitory Ras inhibited nicotine-induced ERK phosphorylation. A calmodulin antagonist, a CaM kinase inhibitor, a MAP kinase kinase inhibitor inhibited nicotine-induced ERK and CREB phosphorylation. The time course of the phosphorylation of CREB induced by nicotine was similar to that of ERK induced by nicotine. These results suggest that non-alpha7 nAChRs are involved in nicotine-induced ERK phosphorylation through CaM kinase and the Ras-MAP kinase cascade and most of the nicotine-induced CREB phosphorylation is mediated by the ERK phosphorylation in PC12h cells.
authors.affiliation: Department of Pharmacology, Nara Medical University, Kashihara, Nara, Japan. hnakayam@naramed-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Nakayama
authors.forename: T
authors.initials: T
authors.lastname: Numakawa
authors.forename: T
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: H
authors.initials: H
authors.lastname: Hatanaka
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002038:Bungarotoxins / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D007306:Insecticides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014403:Tubocurarine / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D000157:Aconitine; D001596:Benzylamines; D002038:Bungarotoxins; D002118:Calcium; D002121:Calcium Channel Blockers; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002147:Calmodulin; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D018738:Hexamethonium; D007306:Insecticides; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D020932:Nerve Growth Factor; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D009543:Nifedipine; D011188:Potassium; D011978:Receptors, Nicotinic; D013449:Sulfonamides; D014403:Tubocurarine; D018631:ras Proteins; C072105:KN 93; D000096926:Benzenesulfonamides; C054634:methyllycaconitine; C017967:W 7