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Article ; Online: CXCR2 signaling protects oligodendrocyte progenitor cells from IFN-γ/CXCL10-mediated apoptosis.

Tirotta, Emanuele / Ransohoff, Richard M / Lane, Thomas E

2011 Volume 59, Issue 10, Page(s) 1518–1528

Abstract: Infiltration of activated lymphocytes into the central nervous system (CNS) is potentially harmful by damaging resident cells through release of cytokines. Among these is IFN-γ that is secreted by activated natural killer (NK) cells and T lymphocytes and ...

Abstract	Infiltration of activated lymphocytes into the central nervous system (CNS) is potentially harmful by damaging resident cells through release of cytokines. Among these is IFN-γ that is secreted by activated natural killer (NK) cells and T lymphocytes and can exert a cytotoxic effect on resident glial populations including oligodendrocytes. Here we show that treatment of mouse oligodendrocyte progenitor cell (OPC)-enriched cultures with IFN-γ resulted in a dose-dependent increase in apoptosis. IFN-γ-induced apoptosis is mediated, in part, through induction of the CXC chemokine ligand 10 (CXCL10; IP-10) from cultured OPCs. Treatment of OPCs with CXCL10 resulted in cell death in a concentration-dependent manner and IFN-γ-treatment of CXCL10-/- OPCs resulted in >50% reduction in cell death. Further, treatment of CXCR3-/- OPC cultures with either IFN-γ or CXCL10 resulted in reduced cell death supporting an important role for CXCL10 signaling in IFN-γ-mediated OPC apoptosis. Data is also provided demonstrating that signaling through CXCR2 protects either IFN-γ or CXCL10-treated OPC cultures from apoptosis and this effect is abolished in CXCR2-/- OPCs. CXCR2-mediated protection from apoptosis is associated with impaired cleavage of caspase 3 and elevated expression of the anti-apoptotic protein Bcl-2. These findings demonstrate a previously unappreciated role for CXCL10 in contributing to neuropathology by promoting oligodendrocyte apoptosis and emphasize the potential relevance in targeting CXCL10 in treating human demyelinating diseases including multiple sclerosis (MS).
MeSH term(s)	Animals ; Animals, Newborn ; Antigens/metabolism ; Apoptosis/drug effects ; Apoptosis/genetics ; Apoptosis/physiology ; Cells, Cultured ; Chemokine CXCL10/deficiency ; Chemokine CXCL10/pharmacology ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay/methods ; In Situ Nick-End Labeling/methods ; Interferon-gamma/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oligodendroglia/drug effects ; Oligodendroglia/metabolism ; Proteoglycans/metabolism ; Receptors, CXCR3/genetics ; Receptors, CXCR3/metabolism ; Receptors, Interleukin-8B/genetics ; Receptors, Interleukin-8B/metabolism ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Stem Cells/drug effects ; Stem Cells/metabolism ; Time Factors
Chemical Substances	Antigens ; Chemokine CXCL10 ; Cxcl10 protein, mouse ; Cxcr3 protein, mouse ; Proteoglycans ; Receptors, CXCR3 ; Receptors, Interleukin-8B ; chondroitin sulfate proteoglycan 4 ; Interferon-gamma (82115-62-6)
Keywords	covid19
Language	English
Publishing date	2011-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.21195
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 2345: Show issues

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Article ; Online: IFN-γ-induced apoptosis of human embryonic stem cell derived oligodendrocyte progenitor cells is restricted by CXCR2 signaling.

Tirotta, Emanuele / Kirby, Leslie A / Hatch, Maya N / Lane, Thomas E

Stem cell research

2012 Volume 9, Issue 3, Page(s) 208–217

Abstract: Engraftment of human embryonic stem cell (hESC)-derived OPCs in animal models of demyelination results in remyelination and clinical recovery, supporting the feasibility of cell replacement therapies in promoting repair of damaged neural tissue. A ... ...

Abstract	Engraftment of human embryonic stem cell (hESC)-derived OPCs in animal models of demyelination results in remyelination and clinical recovery, supporting the feasibility of cell replacement therapies in promoting repair of damaged neural tissue. A critical gap in our understanding of the mechanisms associated with repair revolves around the effects of the local microenvironment on transplanted cell survival. We have determined that treatment of human ESC-derived OPCs with the pleiotropic cytokine IFN-γ promotes apoptosis that is associated with mitochondrial cytochrome c released into the cytosol with subsequent caspase 3 activation. IFN-γ-induced apoptosis is mediated, in part, by secretion of the CXC chemokine ligand 10 (CXCL10) from IFN-γ-treated cells. Signaling through the chemokine receptor CXCR2 by the ligand CXCL1 functions in a tonic manner by muting apoptosis and this is associated with reduced levels of cytosolic cytochrome c and impaired cleavage of caspase 3. These findings support a role for both IFN-γ and CXCL10 in contributing to neuropathology by promoting OPC apoptosis. In addition, these data suggest that hOPCs used for therapeutic treatment for human neurologic disease/damage are susceptible to death through exposure to local inflammatory cytokines present within the inflammatory milieu.
MeSH term(s)	Apoptosis ; Cell Line ; Chemokine CXCL10/metabolism ; Cytochromes c/metabolism ; Embryonic Stem Cells/cytology ; Embryonic Stem Cells/metabolism ; Humans ; Interferon-gamma/metabolism ; Oligodendroglia/cytology ; Oligodendroglia/metabolism ; Receptors, Interleukin-8B/genetics ; Receptors, Interleukin-8B/metabolism ; Signal Transduction
Chemical Substances	Chemokine CXCL10 ; Receptors, Interleukin-8B ; Interferon-gamma (82115-62-6) ; Cytochromes c (9007-43-6)
Language	English
Publishing date	2012-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1876-7753
ISSN (online)	1876-7753
DOI	10.1016/j.scr.2012.06.005
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Article ; Online: CXCR2 signaling protects oligodendrocytes and restricts demyelination in a mouse model of viral-induced demyelination.

Hosking, Martin P / Tirotta, Emanuele / Ransohoff, Richard M / Lane, Thomas E

PloS one

2010 Volume 5, Issue 6, Page(s) e11340

Abstract: Background: The functional role of ELR-positive CXC chemokines during viral-induced demyelination was assessed. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute ... ...

Abstract	Background: The functional role of ELR-positive CXC chemokines during viral-induced demyelination was assessed. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute encephalomyelitis that evolves into a chronic demyelinating disease, modeling white matter pathology observed in the human demyelinating disease Multiple Sclerosis. Methodology/principal findings: JHMV infection induced the rapid and sustained expression of transcripts specific for the ELR+ chemokine ligands CXCL1 and CXCL2, as well as their binding receptor CXCR2, which was enriched within the spinal cord during chronic infection. Inhibiting CXCR2 signaling with neutralizing antiserum significantly (p<0.03) delayed clinical recovery. Moreover, CXCR2 neutralization was associated with an increase in the severity of demyelination that was independent of viral recrudescence or modulation of neuroinflammation. Rather, blocking CXCR2 was associated with increased numbers of apoptotic cells primarily within white matter tracts, suggesting that oligodendrocytes were affected. JHMV infection of enriched oligodendrocyte progenitor cell (OPC) cultures revealed that apoptosis was associated with elevated expression of cleaved caspase 3 and muted Bcl-2 expression. Inclusion of CXCL1 within JHMV infected cultures restricted caspase 3 cleavage and increased Bcl-2 expression that was associated with a significant (p<0.001) decrease in apoptosis. CXCR2 deficient oligodendrocytes were refractory to CXCL1 mediated protection from JHMV-induced apoptosis, readily activating caspase 3 and down regulating Bcl-2. Conclusion/significance: These findings highlight a previously unappreciated role for CXCR2 signaling in protecting oligodendrocyte lineage cells from apoptosis during inflammatory demyelination initiated by viral infection of the CNS.
MeSH term(s)	Animals ; Apoptosis ; Chemokine CXCL1/metabolism ; Chemokine CXCL2/metabolism ; Disease Models, Animal ; Ligands ; Mice ; Mice, Inbred C57BL ; Multiple Sclerosis/metabolism ; Multiple Sclerosis/pathology ; Multiple Sclerosis/virology ; Murine hepatitis virus/physiology ; Oligodendroglia/metabolism ; Oligodendroglia/pathology ; Polymerase Chain Reaction ; Receptors, Interleukin-8B/metabolism ; Signal Transduction ; Up-Regulation
Chemical Substances	Chemokine CXCL1 ; Chemokine CXCL2 ; Ligands ; Receptors, Interleukin-8B
Keywords	covid19
Language	English
Publishing date	2010-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0011340
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Double Stereodifferentiation in the Asymmetric Dihydroxylation of Optically Active Olefins.

Righi, Giuliana / Bovicelli, Paolo / Tirotta, Ilaria / Sappino, Carla / Mandic', Emanuela

Chirality

2016 Volume 28, Issue 5, Page(s) 387–393

Abstract: A study of the stereochemical control on the asymmetric dihydroxylation of the double bond of optically active vinyl epoxides and their derivatives (bromo derivatives, azido derivatives, and vinyl aziridines) was carried out and the obtained results are ... ...

Abstract	A study of the stereochemical control on the asymmetric dihydroxylation of the double bond of optically active vinyl epoxides and their derivatives (bromo derivatives, azido derivatives, and vinyl aziridines) was carried out and the obtained results are herein reported. The most interesting results were obtained on trans α,β-unsaturated epoxy esters, which were successfully converted with a diastereomeric ratio >80% into the corresponding diols using either the matched or the mismatched conditions, depending on the ligand used. Unprotected bromo derivatives and unprotected aziridines did not afford significant results, while for the protected bromo derivatives, azido derivatives, and N-Boc protected aziridines the matched conditions led to a diastereomeric ratio >95%. Chirality 28:387-393, 2016. © 2016 Wiley Periodicals, Inc.
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1011639-4
ISSN	1520-636X ; 0899-0042
ISSN (online)	1520-636X
ISSN	0899-0042
DOI	10.1002/chir.22587
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Zs.A 2594: Show issues

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Article ; Online: Cell replacement therapies to promote remyelination in a viral model of demyelination.

Tirotta, Emanuele / Carbajal, Kevin S / Schaumburg, Chris S / Whitman, Lucia / Lane, Thomas E

Journal of neuroimmunology

2010 Volume 224, Issue 1-2, Page(s) 101–107

Abstract: Persistent infection of the central nervous system (CNS) of mice with the neuroadapted JHM strain of mouse hepatitis (MHV) is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and ... ...

Abstract	Persistent infection of the central nervous system (CNS) of mice with the neuroadapted JHM strain of mouse hepatitis (MHV) is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Although extensive demyelination occurs in mice persistently infected with MHV there is only limited remyelination. Therefore, the MHV model of demyelination is a relevant model for studying disease and evaluating therapeutic approaches to protect cells of the oligodendrocyte lineage and promote remyelination. This concept is further highlighted as the etiology of MS remains enigmatic, but viruses have long been considered as potential triggering agents in initiating and/or maintaining MS symptoms. As such, understanding mechanisms associated with promoting repair within the CNS in the context of a persistent viral infection is critical given the possible viral etiology of MS. This review focuses on recent studies using either mouse neural stem cells (NSCs) or human oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem cell (hESC) to promote remyelination in mice persistently infected with MHV. In addition, the potential role for chemokines in positional migration of transplanted cells is addressed.
MeSH term(s)	Animals ; Cell Lineage/immunology ; Coronavirus Infections/immunology ; Coronavirus Infections/pathology ; Coronavirus Infections/therapy ; Demyelinating Diseases/pathology ; Demyelinating Diseases/therapy ; Demyelinating Diseases/virology ; Disease Models, Animal ; Encephalitis, Viral/immunology ; Encephalitis, Viral/pathology ; Encephalitis, Viral/therapy ; Humans ; Mice ; Murine hepatitis virus/immunology ; Nerve Fibers, Myelinated/immunology ; Nerve Fibers, Myelinated/metabolism ; Nerve Fibers, Myelinated/pathology ; Nerve Regeneration/immunology ; Stem Cell Transplantation/methods ; Stem Cell Transplantation/trends
Keywords	covid19
Language	English
Publishing date	2010-06-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	8335-5
ISSN	1872-8421 ; 0165-5728
ISSN (online)	1872-8421
ISSN	0165-5728
DOI	10.1016/j.jneuroim.2010.05.013
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Zs.A 1646: Show issues

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Article ; Online: Dopamine D(2) Antagonist-Induced Striatal Nur77 Expression Requires Activation of mGlu5 Receptors by Cortical Afferents.

Maheux, Jérôme / St-Hilaire, Michel / Voyer, David / Tirotta, Emanuele / Borrelli, Emiliana / Rouillard, Claude / Rompré, Pierre-Paul / Lévesque, Daniel

Frontiers in pharmacology

2012 Volume 3, Page(s) 153

Abstract: Dopamine D(2) receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, ... ...

Abstract	Dopamine D(2) receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, as readout to explore the role of dopamine, glutamate, and adenosine receptors in the effect of a dopamine D(2) antagonist in the striatum. First, we investigated D(2) antagonist-induced Nur77 mRNA in D(2L) receptor knockout mice. Surprisingly, deletion of the D(2L) receptor isoform did not reduce eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Next, we tested if an ibotenic acid-induced cortical lesion could block the effect of eticlopride on Nur77 expression. Cortical lesions strongly reduced eticlopride-induced striatal upregulation of Nur77 mRNA. Then, we investigated if glutamatergic neurotransmission could modulate eticlopride-induced Nur77 expression. A combination of a metabotropic glutamate type 5 (mGlu5) and adenosine A(2A) receptor antagonists abolished eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Direct modulation of Nur77 expression by striatal glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that blockade of postsynaptic D(2) receptors is not sufficient to trigger striatal transcriptional activity and that interaction with corticostriatal presynaptic D(2) receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum is required. Thus, these results uncover an unappreciated role of presynaptic D(2) heteroreceptors and support a prominent role of glutamate in the effect of D(2) antagonists.
Language	English
Publishing date	2012-08-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812 ; 1663-9812
ISSN (online)	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2012.00153
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Epstein-Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis.

Tirotta, Emanuele / Duncker, Patrick / Oak, Jean / Klaus, Suzi / Tsukamoto, Michelle R / Gov, Lanny / Lane, Thomas E

Journal of neuroimmunology

2012 Volume 254, Issue 1-2, Page(s) 110–116

Abstract: Epstein-Barr virus-induced gene 3 (EBI3) associates with p28 and p35 to form the immunomodulatory cytokines IL-27 and IL-35, respectively. Infection of EBI3-/- mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) resulted in increased ... ...

Abstract	Epstein-Barr virus-induced gene 3 (EBI3) associates with p28 and p35 to form the immunomodulatory cytokines IL-27 and IL-35, respectively. Infection of EBI3-/- mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality that was not associated with impaired ability to control viral replication but enhanced T cell and macrophage infiltration into the CNS. IFN-γ secretion from virus-specific CD4+ and CD8+ T cells isolated from infected EBI3-/- mice was augmented while IL-10 expression muted in comparison to infected WT mice. These data demonstrate a regulatory role for EBI3-associated cytokines in controlling host responses following CNS viral infection.
MeSH term(s)	Animals ; Antigens, CD/metabolism ; CD8 Antigens/metabolism ; Coronavirus Infections/complications ; Cytokines/genetics ; Cytokines/metabolism ; Disease Models, Animal ; Encephalomyelitis/etiology ; Encephalomyelitis/immunology ; Encephalomyelitis/mortality ; Encephalomyelitis/pathology ; Flow Cytometry ; Gene Expression Regulation, Viral/genetics ; Glial Fibrillary Acidic Protein/metabolism ; Interferon-gamma/metabolism ; Interleukin-10/metabolism ; Lymphocyte Activation/genetics ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Minor Histocompatibility Antigens ; RNA, Messenger/metabolism ; Receptors, Cytokine/deficiency ; Receptors, Cytokine/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/virology ; Time Factors
Chemical Substances	Antigens, CD ; CD8 Antigens ; Cytokines ; Ebi3 protein, mouse ; Glial Fibrillary Acidic Protein ; Minor Histocompatibility Antigens ; RNA, Messenger ; Receptors, Cytokine ; Interleukin-10 (130068-27-8) ; Interferon-gamma (82115-62-6)
Keywords	covid19
Language	English
Publishing date	2012-10-26
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	8335-5
ISSN	1872-8421 ; 0165-5728
ISSN (online)	1872-8421
ISSN	0165-5728
DOI	10.1016/j.jneuroim.2012.10.005
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Zs.A 1646: Show issues

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Article ; Online: CXCR2 signaling protects oligodendrocytes and restricts demyelination in a mouse model of viral-induced demyelination.

Martin P Hosking / Emanuele Tirotta / Richard M Ransohoff / Thomas E Lane

PLoS ONE, Vol 5, Iss 6, p e

2010 Volume 11340

Abstract: The functional role of ELR-positive CXC chemokines during viral-induced demyelination was assessed. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute encephalomyelitis that ... ...

Abstract	The functional role of ELR-positive CXC chemokines during viral-induced demyelination was assessed. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute encephalomyelitis that evolves into a chronic demyelinating disease, modeling white matter pathology observed in the human demyelinating disease Multiple Sclerosis.JHMV infection induced the rapid and sustained expression of transcripts specific for the ELR+ chemokine ligands CXCL1 and CXCL2, as well as their binding receptor CXCR2, which was enriched within the spinal cord during chronic infection. Inhibiting CXCR2 signaling with neutralizing antiserum significantly (p<0.03) delayed clinical recovery. Moreover, CXCR2 neutralization was associated with an increase in the severity of demyelination that was independent of viral recrudescence or modulation of neuroinflammation. Rather, blocking CXCR2 was associated with increased numbers of apoptotic cells primarily within white matter tracts, suggesting that oligodendrocytes were affected. JHMV infection of enriched oligodendrocyte progenitor cell (OPC) cultures revealed that apoptosis was associated with elevated expression of cleaved caspase 3 and muted Bcl-2 expression. Inclusion of CXCL1 within JHMV infected cultures restricted caspase 3 cleavage and increased Bcl-2 expression that was associated with a significant (p<0.001) decrease in apoptosis. CXCR2 deficient oligodendrocytes were refractory to CXCL1 mediated protection from JHMV-induced apoptosis, readily activating caspase 3 and down regulating Bcl-2.These findings highlight a previously unappreciated role for CXCR2 signaling in protecting oligodendrocyte lineage cells from apoptosis during inflammatory demyelination initiated by viral infection of the CNS.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2010-06-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Oligodendrocytes as regulators of neuronal networks during early postnatal development.

Doretto, Sandrine / Malerba, Monica / Ramos, Maria / Ikrar, Taruna / Kinoshita, Chisato / De Mei, Claudia / Tirotta, Emanuele / Xu, Xiangmin / Borrelli, Emiliana

PloS one

2011 Volume 6, Issue 5, Page(s) e19849

Abstract: Oligodendrocytes are the glial cells responsible for myelin formation. Myelination occurs during the first postnatal weeks and, in rodents, is completed during the third week after birth. Myelin ensures the fast conduction of the nerve impulse; in the ... ...

Abstract	Oligodendrocytes are the glial cells responsible for myelin formation. Myelination occurs during the first postnatal weeks and, in rodents, is completed during the third week after birth. Myelin ensures the fast conduction of the nerve impulse; in the adult, myelin proteins have an inhibitory role on axon growth and regeneration after injury. During brain development, oligodendrocytes precursors originating in multiple locations along the antero-posterior axis actively proliferate and migrate to colonize the whole brain. Whether the initial interactions between oligodendrocytes and neurons might play a functional role before the onset of myelination is still not completely elucidated. In this article, we addressed this question by transgenically targeted ablation of proliferating oligodendrocytes during cerebellum development. Interestingly, we show that depletion of oligodendrocytes at postnatal day 1 (P1) profoundly affects the establishment of cerebellar circuitries. We observed an impressive deregulation in the expression of molecules involved in axon growth, guidance and synaptic plasticity. These effects were accompanied by an outstanding increase of neurofilament staining observed 4 hours after the beginning of the ablation protocol, likely dependent from sprouting of cerebellar fibers. Oligodendrocyte ablation modifies localization and function of ionotropic glutamate receptors in Purkinje neurons. These results show a novel oligodendrocyte function expressed during early postnatal brain development, where these cells participate in the formation of cerebellar circuitries, and influence its development.
MeSH term(s)	Animals ; Mice ; Mice, Transgenic ; Nerve Net ; Oligodendroglia/physiology
Language	English
Publishing date	2011-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0019849
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Article ; Online: Contribution of Kv1.2 voltage-gated potassium channel to D2 autoreceptor regulation of axonal dopamine overflow.

Fulton, Stephanie / Thibault, Dominic / Mendez, Jose A / Lahaie, Nicolas / Tirotta, Emanuele / Borrelli, Emiliana / Bouvier, Michel / Tempel, Bruce L / Trudeau, Louis-Eric

The Journal of biological chemistry

2011 Volume 286, Issue 11, Page(s) 9360–9372

Abstract: Impairments in axonal dopamine release are associated with neurological disorders such as schizophrenia and attention deficit hyperactivity disorder and pathophysiological conditions promoting drug abuse and obesity. The D2 dopamine autoreceptor (D2-AR) ... ...

Abstract	Impairments in axonal dopamine release are associated with neurological disorders such as schizophrenia and attention deficit hyperactivity disorder and pathophysiological conditions promoting drug abuse and obesity. The D2 dopamine autoreceptor (D2-AR) exerts tight regulatory control of axonal dopamine (DA) release through a mechanism suggested to involve K(+) channels. To evaluate the contribution of Kv1 voltage-gated potassium channels of the Shaker gene family to the regulation of axonal DA release by the D2-AR, the present study employed expression analyses, real time measurements of striatal DA overflow, K(+) current measurements and immunoprecipitation assays. Kv1.1, -1.2, -1.3, and -1.6 mRNA and protein were detected in midbrain DA neurons purified by fluorescence-activated cell sorting and in primary DA neuron cultures. In addition, Kv1.1, -1.2, and -1.6 were localized to DA axonal processes in the dorsal striatum. By means of fast scan cyclic voltammetry in striatal slice preparations, we found that the inhibition of stimulation-evoked DA overflow by a D2 agonist was attenuated by Kv1.1, -1.2, and -1.6 toxin blockers. A particular role for the Kv1.2 subunit in the process whereby axonal D2-AR inhibits DA overflow was established with the use of a selective Kv1.2 blocker and Kv1.2 knock-out mice. Moreover, we demonstrate the ability of D2-AR activation to increase Kv1.2 currents in co-transfected cells and its reliance on Gβγ subunit signaling along with the physical coupling of D2-AR and Kv1.2-containing channels in striatal tissue. These findings underline the contribution of Kv1.2 in the regulation of nigrostriatal DA release by the D2-AR and thereby offer a novel mechanism by which DA release is regulated.
MeSH term(s)	Animals ; Axons/metabolism ; Corpus Striatum/metabolism ; Dopamine/genetics ; Dopamine/metabolism ; Dopamine Agonists/pharmacology ; Kv1.2 Potassium Channel/genetics ; Kv1.2 Potassium Channel/metabolism ; Male ; Mice ; Mice, Knockout ; Receptors, Dopamine D2/genetics ; Receptors, Dopamine D2/metabolism ; Signal Transduction/drug effects ; Signal Transduction/physiology
Chemical Substances	Dopamine Agonists ; Kv1.2 Potassium Channel ; Receptors, Dopamine D2 ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2011-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M110.153262
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