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

Bronwyn Kivell; Zeljko Uzelac; Santhanalakshmi Sundaramurthy; Jeyaganesh Rajamanickam; Amy Ewald; Vladimir Chefer; Vanaja Jaligam; Elizabeth Bolan; Bridget Simonson; Balasubramaniam Annamalai; Padmanabhan Mannangatti; Thomas E. Prisinzano; Ivone Gomes; Lakshmi A. Devi; Lankupalle D. Jayanthi; Harald H. Sitte; Sammanda Ramamoorthy; Toni S. Shippenberg

doi:10.1016/j.neuropharm.2014.07.016

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

Bronwyn Kivell, Zeljko Uzelac, Santhanalakshmi Sundaramurthy, Jeyaganesh Rajamanickam, Amy Ewald, Vladimir Chefer, Vanaja Jaligam, Elizabeth Bolan, Bridget Simonson, Balasubramaniam Annamalai, Padmanabhan Mannangatti, Thomas E. Prisinzano, Ivone Gomes, Lakshmi A. Devi, Lankupalle D. Jayanthi, Harald H. Sitte, Sammanda Ramamoorthy, Toni S. Shippenberg

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

Abstract

Salvinorin A (SalA), a selective κ-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 V_max 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.

Original language	English
Pages (from-to)	228-240
Number of pages	13
Journal	Neuropharmacology
Volume	86
DOIs	https://doi.org/10.1016/j.neuropharm.2014.07.016
State	Published - Aug 19 2014

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health and National Institute on Drug Abuse Intramural Research Program (T.S.S), NIH grants, MH083928 , MH091633 (S.R), DA018151 (T.E.P), DA019521 , DA08863 , GM071558 (L.A.D.), The Health Research Council of New Zealand (B.K) and Austrian Science Fund/FWF , P23658 (H.H.S). CCRP-YFP was kindly provided by Dr Michel Bouvier (University of Montreal). DAT constructs were provided by Dr. Jonathan Javitch.

Keywords

Dopamine transporter
Dysphoric
Kappa opioid receptor
Pro-depressant
Salvinorin A
Serotonin transporter
Trafficking

ASJC Scopus subject areas

Pharmacology
Cellular and Molecular Neuroscience

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10.1016/j.neuropharm.2014.07.016

Cite this

Kivell, B., Uzelac, Z., Sundaramurthy, S., Rajamanickam, J., Ewald, A., Chefer, V., Jaligam, V., Bolan, E., Simonson, B., Annamalai, B., Mannangatti, P., Prisinzano, T. E., Gomes, I., Devi, L. A., Jayanthi, L. D., Sitte, H. H., Ramamoorthy, S., & Shippenberg, T. S. (2014). Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism. Neuropharmacology, 86, 228-240. https://doi.org/10.1016/j.neuropharm.2014.07.016

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title = "Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism",

abstract = "Salvinorin A (SalA), a selective κ-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.",

keywords = "Dopamine transporter, Dysphoric, Kappa opioid receptor, Pro-depressant, Salvinorin A, Serotonin transporter, Trafficking",

author = "Bronwyn Kivell and Zeljko Uzelac and Santhanalakshmi Sundaramurthy and Jeyaganesh Rajamanickam and Amy Ewald and Vladimir Chefer and Vanaja Jaligam and Elizabeth Bolan and Bridget Simonson and Balasubramaniam Annamalai and Padmanabhan Mannangatti and Prisinzano, {Thomas E.} and Ivone Gomes and Devi, {Lakshmi A.} and Jayanthi, {Lankupalle D.} and Sitte, {Harald H.} and Sammanda Ramamoorthy and Shippenberg, {Toni S.}",

note = "Funding Information: This work was supported by the National Institutes of Health and National Institute on Drug Abuse Intramural Research Program (T.S.S), NIH grants, MH083928 , MH091633 (S.R), DA018151 (T.E.P), DA019521 , DA08863 , GM071558 (L.A.D.), The Health Research Council of New Zealand (B.K) and Austrian Science Fund/FWF , P23658 (H.H.S). CCRP-YFP was kindly provided by Dr Michel Bouvier (University of Montreal). DAT constructs were provided by Dr. Jonathan Javitch. ",

year = "2014",

month = aug,

day = "19",

doi = "10.1016/j.neuropharm.2014.07.016",

language = "English",

volume = "86",

pages = "228--240",

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Kivell, B, Uzelac, Z, Sundaramurthy, S, Rajamanickam, J, Ewald, A, Chefer, V, Jaligam, V, Bolan, E, Simonson, B, Annamalai, B, Mannangatti, P, Prisinzano, TE, Gomes, I, Devi, LA, Jayanthi, LD, Sitte, HH, Ramamoorthy, S & Shippenberg, TS 2014, 'Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism', Neuropharmacology, vol. 86, pp. 228-240. https://doi.org/10.1016/j.neuropharm.2014.07.016

TY - JOUR

T1 - Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism

AU - Kivell, Bronwyn

AU - Uzelac, Zeljko

AU - Sundaramurthy, Santhanalakshmi

AU - Rajamanickam, Jeyaganesh

AU - Ewald, Amy

AU - Chefer, Vladimir

AU - Jaligam, Vanaja

AU - Bolan, Elizabeth

AU - Simonson, Bridget

AU - Annamalai, Balasubramaniam

AU - Mannangatti, Padmanabhan

AU - Prisinzano, Thomas E.

AU - Gomes, Ivone

AU - Devi, Lakshmi A.

AU - Jayanthi, Lankupalle D.

AU - Sitte, Harald H.

AU - Ramamoorthy, Sammanda

AU - Shippenberg, Toni S.

N1 - Funding Information: This work was supported by the National Institutes of Health and National Institute on Drug Abuse Intramural Research Program (T.S.S), NIH grants, MH083928 , MH091633 (S.R), DA018151 (T.E.P), DA019521 , DA08863 , GM071558 (L.A.D.), The Health Research Council of New Zealand (B.K) and Austrian Science Fund/FWF , P23658 (H.H.S). CCRP-YFP was kindly provided by Dr Michel Bouvier (University of Montreal). DAT constructs were provided by Dr. Jonathan Javitch.

PY - 2014/8/19

Y1 - 2014/8/19

N2 - Salvinorin A (SalA), a selective κ-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.

AB - Salvinorin A (SalA), a selective κ-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.

KW - Dopamine transporter

KW - Dysphoric

KW - Kappa opioid receptor

KW - Pro-depressant

KW - Salvinorin A

KW - Serotonin transporter

KW - Trafficking

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UR - http://www.scopus.com/inward/citedby.url?scp=84907359962&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2014.07.016

DO - 10.1016/j.neuropharm.2014.07.016

M3 - Article

C2 - 25107591

AN - SCOPUS:84907359962

SN - 0028-3908

VL - 86

SP - 228

EP - 240

JO - Neuropharmacology

JF - Neuropharmacology

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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