title: Protein kinase A activation down-regulates, whereas extracellular signal-regulated kinase activation up-regulates sigma-1 receptors in B-104 cells: Implication for neuroplasticity.
abstract: The sigma-1 receptor (Sig-1R) can bind psychostimulants and was shown to be up-regulated in the brain of methamphetamine self-administering rats. Up-regulation of Sig-1Rs has been implicated in neuroplasticity. However, the mechanism(s) whereby Sig-1Rs are up-regulated by psychostimulants is unknown. Here, we employed a neuroblastoma cell line B-104, devoid of dopamine receptors and transporter, and examined the effects of psychostimulants as well as cAMP on the expression of Sig-1Rs in this cell line, with a specific goal to identify signal transduction pathway(s) that may regulate Sig-1R expression. Chronic treatments of B-104 cells with physiological concentrations of cocaine or methamphetamine failed to alter the expression of Sig-1Rs. N6,2'-O-Dibutyryl-cAMP (dB-cAMP), when used at 0.5 mM, caused a down-regulation of Sig-1Rs that could be blocked by a protein kinase A (PKA) inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89). However, dB-cAMP, when used at 2 mM, caused an up-regulation of Sig-1Rs that was insensitive to the H-89 blockade but was partially blocked by an extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase inhibitor PD98059 (2'-amino-3'-methoxyflavone). Furthermore, 2 mM dB-cAMP induced an ERK phosphorylation lasting at least 90 min, at which time the phosphorylation caused by 0.5 mM dB-cAMP had already diminished. PD98059, applied 90 min after addition of 2 mM dB-cAMP, attenuated the Sig-1R up-regulation. Our results indicate that cAMP is bimodal in regulating Sig-1R expression: a down-regulation via PKA and an up-regulation via ERK. Results also suggest that psychostimulants may manipulate the cAMP-PKA-Sig-1R and/or the cAMP-ERK-Sig-1R pathways to achieve a neuroplasticity that favors addictive behaviors.
authors.affiliation: Development and Plasticity Section/Cellular Neurobiology Research Branch, Intramural Research Program/National Institute on Drug Abuse/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland, USA.
authors.forename: Gianfrancesco
authors.initials: G
authors.lastname: Cormaci
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.forename: Teruo
authors.initials: T
authors.lastname: Hayashi
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D003042:Cocaine / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008694:Methamphetamine / Q000494:pharmacology; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity / Q000502:physiology*; D051381:Rats; D011954:Receptors, Dopamine / Q000032:analysis; D017480:Receptors, sigma / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000097605:Sigma-1 Receptor
chemical_list: D003042:Cocaine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D050483:Dopamine Plasma Membrane Transport Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D008694:Methamphetamine; D011954:Receptors, Dopamine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one