Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism.

ObservationalPubMedPubMed ✓July 14, 2015PMID: 25107591 DOI

Abstract

Salvinorin A (SalA), a selective -opioid receptor (KOR) agonist, produces dysphoria and pro-depressant like effects. These actions have been attributed to inhibition of striatal dopamine release. The dopamine transporter (DAT) regulates dopamine transmission via uptake of released neurotransmitter. KORs are apposed to DAT in dopamine nerve terminals suggesting an additional target by which SalA modulates dopamine transmission. SalA produced a concentration-dependent, nor-binaltorphimine (BNI)- and pertussis toxin-sensitive increase of ASP(+) accumulation in EM4 cells coexpressing myc-KOR and YFP-DAT, using live cell imaging and the fluorescent monoamine transporter substrate, trans 4-(4-(dimethylamino)-styryl)-N-methylpyridinium) (ASP(+)). Other KOR agonists also increased DAT activity that was abolished by BNI pretreatment. While SalA increased DAT activity, SalA treatment decreased serotonin transporter (SERT) activity and had no effect on norepinephrine transporter (NET) activity. In striatum, SalA increased the Vmax for DAT mediated DA transport and DAT surface expression. SalA up-regulation of DAT function is mediated by KOR activation and the KOR-linked extracellular signal regulated kinase- (ERK1/2) pathway. Co-immunoprecipitation and BRET studies revealed that DAT and KOR exist in a complex. In live cells, DAT and KOR exhibited robust FRET signals under basal conditions. SalA exposure caused a rapid and significant increase of the FRET signal. This suggests that the formation of KOR and DAT complexes is promoted in response to KOR activation. Together, these data suggest that enhanced DA transport and decreased DA release resulting in decreased dopamine signalling may contribute to the dysphoric and pro-depressant like effects of SalA and other KOR agonists.

Authors (18)

LeadSchool of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand; Integrative Neuroscience Section, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.

Medical University Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringerstrasse 13a, A-1090 Vienna, Austria.

Santhanalakshmi SundaramurthyDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.

Jeyaganesh RajamanickamDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.

Amy EwaldSchool of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.

Vladimir CheferIntegrative Neuroscience Section, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.

Vanaja JaligamIntegrative Neuroscience Section, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.

Elizabeth BolanIntegrative Neuroscience Section, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.

Bridget SimonsonSchool of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.

Balasubramaniam AnnamalaiDepartment of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.

Padmanabhan MannangattiDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.

Thomas E PrisinzanoDepartment of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA.

Ivone GomesDepartment of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.

Lakshmi A DeviDepartment of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.

Lankupalle D JayanthiDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.

Harald H SitteMedical University Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringerstrasse 13a, A-1090 Vienna, Austria.

Sammanda RamamoorthyDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: sramamoorthy@vcu.edu.

Toni S ShippenbergIntegrative Neuroscience Section, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.

MeSH Terms

Cell MembraneCorpus StriatumDiterpenes, ClerodaneDopamineDopamine AgentsDopamine Plasma Membrane Transport ProteinsHEK293 CellsHumansMAP Kinase Signaling SystemNorepinephrine Plasma Membrane Transport ProteinsReceptors, Opioid, kappaSerotonin Plasma Membrane Transport Proteinsp38 Mitogen-Activated Protein Kinases

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Metadata

Study TypeObservational

SourcePubMed

Publication DateJuly 14, 2015

Citations0

Data Confidence

100

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