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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aconitine / analogs & derivatives*
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Aconitine / pharmacology
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Animals
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Benzylamines / pharmacology
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Bungarotoxins / metabolism
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Bungarotoxins / pharmacology
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Calcium / metabolism
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Calcium Channel Blockers / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calmodulin / antagonists & inhibitors
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Enzyme Inhibitors / pharmacology
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Hexamethonium / pharmacology
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Insecticides / pharmacology
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / physiology
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism*
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Nerve Growth Factor / pharmacology
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Neurons / cytology
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Neurons / metabolism*
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Nicotine / pharmacology*
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Nicotinic Agonists / pharmacology*
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Nicotinic Antagonists / pharmacology
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Nifedipine / pharmacology
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PC12 Cells
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Phosphorylation
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Potassium / pharmacology
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Rats
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Receptors, Nicotinic / metabolism
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Sulfonamides / pharmacology
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Tubocurarine / pharmacology
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ras Proteins / metabolism
Substances
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Benzylamines
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Bungarotoxins
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Calcium Channel Blockers
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Calmodulin
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Cyclic AMP Response Element-Binding Protein
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Enzyme Inhibitors
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Insecticides
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Nicotinic Agonists
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Nicotinic Antagonists
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Receptors, Nicotinic
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Sulfonamides
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KN 93
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methyllycaconitine
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Hexamethonium
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W 7
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Nicotine
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Nerve Growth Factor
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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ras Proteins
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Nifedipine
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Potassium
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Calcium
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Tubocurarine
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Aconitine