sigma 2-Receptor Regulation of Dopamine Transporter via Activation of Protein Kinase C

George Washington University, Washington, Washington, D.C., United States
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 05/2002; 301(1):306-14. DOI: 10.1124/jpet.301.1.306
Source: PubMed


The elucidation of the mechanisms underlying sigma(2)-receptor activation and signal transduction is crucial to the understanding of sigma(2)-receptor function. Previous studies in our laboratory have demonstrated sigma(2)-receptor-mediated regulation of the dopamine transporter (DAT) as measured by amphetamine-stimulated release of [(3)H]dopamine (DA) from both rat striatal slices and PC12 cells. The regulation of the DAT in the PC12 cell model was dependent upon activation of Ca(2+)/calmodulin-dependent kinase II. We have now studied the second messenger systems involved in sigma(2)-receptor-mediated regulation of amphetamine-stimulated [(3)H]DA release in rat striatal slices, including Ca(2+)/calmodulin-dependent kinase II, protein kinase C, and sources of calcium required for the enhancement of release produced by sigma(2)-receptor activation. The Ca(2+)/calmodulin-dependent kinase II inhibitors 1-[N,O-bis-(5-isoquionolinesulfonyl)]-N-methyl-L-tyrosyl-4-phenylpiperazine and N-[2-[[[3-(4'-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4'-methoxy-benzenesulfonamide phosphate did not significantly affect the (+)-pentazocine-mediated enhancement of amphetamine-stimulated [(3)H]DA release. However, we found that an inhibitor of protein kinase C, 3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl)-1H-pyrrole-2,5-dione, blocks the (+)-pentazocine-mediated enhancement in rat striatal slices. The protein kinase C activator phorbol 12-myristate 13-acetate, but not the inactive isophorbol 4 alpha,9 alpha,12 alpha,13 alpha,20-pentahydroxytiglia-1,6-dien-3-one, enhanced the amphetamine-stimulated [(3)H]DA release comparable to the enhancement seen by (+)-pentazocine alone. Additionally, the L-type voltage-dependent calcium channel inhibitor nitrendipine or prior treatment with thapsigargin, but not the N-type voltage-dependent calcium channel omega-conotoxin MVIIA, attenuated the (+)-pentazocine-mediated enhancement. Together, these data suggest that activation of sigma(2)-receptors results in the regulation of DAT activity via a calcium- and protein kinase C-dependent signaling mechanism.

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    • "Moreover, AC927 pretreatment prevented the dopamine release caused by METH but not the nonspecific dopamine release caused by K ϩ -mediated hyperpolarization. This is consistent with the role of ␴ receptors in regulating DAT function and dopamine release in several in vivo and in vitro studies, including the involvement of Ca 2ϩ -dependent and protein kinase C-mediated mechanisms (Booth and Baldessarini, 1991; Derbez et al., 2002). In addition to modulation of DAT function by ␴ receptors at lower concentrations, AC927 at higher concentrations may act in part as a DAT blocker in NG108-15 cells. "
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    ABSTRACT: Methamphetamine is a highly addictive psychostimulant drug of abuse that causes neurotoxicity with high or repeated dosing. Earlier studies demonstrated the ability of the selective σ receptor ligand N-phenethylpiperidine oxalate (AC927) to attenuate the neurotoxic effects of methamphetamine in vivo. However, the precise mechanisms through which AC927 conveys its protective effects remain to be determined. With the use of differentiated NG108-15 cells as a model system, the effects of methamphetamine on neurotoxic endpoints and mediators such as apoptosis, necrosis, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and dopamine release were examined in the absence and presence of AC927. Methamphetamine at physiologically relevant micromolar concentrations caused apoptosis in NG108-15 cells. At higher concentrations of methamphetamine, necrotic cell death was observed. At earlier time points, methamphetamine caused ROS/RNS generation, which was detected with the fluorigenic substrate 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescin diacetate, acetyl ester, in a concentration- and time-dependent manner. N-Acetylcysteine, catalase, and l-N(G)-monomethyl arginine citrate inhibited the ROS/RNS fluorescence signal induced by methamphetamine, which suggests the formation of hydrogen peroxide and RNS. Exposure to methamphetamine also stimulated the release of dopamine from NG108-15 cells into the culture medium. AC927 attenuated methamphetamine-induced apoptosis, necrosis, ROS/RNS generation, and dopamine release in NG108-15 cells. Together, the data suggest that modulation of σ receptors can mitigate methamphetamine-induced cytotoxicity, ROS/RNS generation, and dopamine release in cultured cells.
    Preview · Article · Nov 2011 · Molecular pharmacology
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    • "Second, σ receptors are present in the basal ganglia and affect motor function (Bouchard and Quirion, 1997; Walker et al., 1993), indicating their potential involvement in the locomotor stimulant effects of METH. Third, σ receptors are present on dopamine and 5-HT neurons, which are damaged by neurotoxic doses of METH, and can modulate their function (Bastianetto et al., 1995; Derbez et al., 2002; Campbell et al., 1989). Fourth, σ receptors participate in cell death pathways in tumor cells (Bowen, 2000), suggesting their possible contribution in METH-induced neurotoxic cascades. "
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    ABSTRACT: Methamphetamine (METH) is a highly addictive psychostimulant drug of abuse. Low and high dose administration of METH leads to locomotor stimulation, and dopaminergic and serotonergic neurotoxicity, respectively. The behavioral stimulant and neurotoxic effects of METH can contribute to addiction and other neuropsychiatric disorders, thus necessitating the identification of potential pharmacotherapeutics against these effects produced by METH. METH binds to σ receptors at physiologically relevant concentrations. Also, σ receptors are present on and can modulate dopaminergic and serotonergic neurons. Therefore, σ receptors provide a viable target for the development of pharmacotherapeutics against the adverse effects of METH. In the present study, CM156, a σ receptor ligand with high affinity and selectivity for σ receptors over 80 other non-σ binding sites, was evaluated against METH-induced stimulant, hyperthermic, and neurotoxic effects. Pretreatment of male, Swiss Webster mice with CM156 dose dependently attenuated the locomotor stimulation, hyperthermia, striatal dopamine and serotonin depletions, and striatal dopamine and serotonin transporter reductions produced by METH, without significant effects of CM156 on its own. These results demonstrate the ability of a highly selective σ ligand to mitigate the effects of METH.
    Full-text · Article · Oct 2011 · Neuropharmacology
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    • "METH acts through DAT and vesicular monoamine transporter 2 (VMAT2) to cause excessive release of dopamine into the cytoplasm and synapse [25, 26], which is thought to be one of the initiating factors in METH’s neurotoxic cascade. σ Receptor agonists have been shown to facilitate dopamine release, through both σ-1 and σ-2 receptors [11-14]. "
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    ABSTRACT: Methamphetamine (METH) is a widely abused substance world over. Currently, there is no effective pharmacotherapy to treat its effects. This necessitates identification of potential novel therapeutic targets. METH interacts with sigma (σ) receptors at physiologically relevant micromolar concentrations. In addition, σ receptors are present in organs like the brain, heart, and lungs at which METH acts. Additionally, σ receptors have been implicated in various acute and subchronic effects like locomotor stimulation, development of sensitization and neurotoxicity, where σ receptor antagonists attenuate these effects. σ Receptors may also have a role in METH-induced psychiatric complications such as depression, psychosis, cognitive and motor deficits. The neurotoxic effects of METH, which are cause for concern, can be prevented by σ receptor antagonists in mice. Mechanistically, METH-induced neurotoxicity involves factors like dopamine release, oxidative stress, endoplasmic reticulum stress, activation of mitochondrial death cascades, glutamate release, apoptosis, microglial activation, and hyperthermia. This review compiles studies from the literature that suggests an important role for σ receptors in many of the mechanisms of METH-induced neurotoxicity.
    Full-text · Article · Mar 2011 · DNA research: an international journal for rapid publication of reports on genes and genomes
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