RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion

Jun Ding; Jaime N Guzman; Tatiana Tkatch; Songhai Chen; Joshua A Goldberg; Philip J Ebert; Pat Levitt; Charles J Wilson; Heidi E Hamm; D James Surmeier

doi:10.1038/nn1700

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RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion

Journal article

Peer reviewed

RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion

Jun Ding, Jaime N Guzman, Tatiana Tkatch, Songhai Chen, Joshua A Goldberg, Philip J Ebert, Pat Levitt, Charles J Wilson, Heidi E Hamm and D James Surmeier

Nature neuroscience, Vol.9(6), pp.832-842

06/2006

DOI: 10.1038/nn1700

PMID: 16699510

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Abstract

Parkinson disease is a neurodegenerative disorder whose symptoms are caused by the loss of dopaminergic neurons innervating the striatum. As striatal dopamine levels fall, striatal acetylcholine release rises, exacerbating motor symptoms. This adaptation is commonly attributed to the loss of interneuronal regulation by inhibitory D(2) dopamine receptors. Our results point to a completely different, new mechanism. After striatal dopamine depletion, D(2) dopamine receptor modulation of calcium (Ca(2+)) channels controlling vesicular acetylcholine release in interneurons was unchanged, but M(4) muscarinic autoreceptor coupling to these same channels was markedly attenuated. This adaptation was attributable to the upregulation of RGS4-an autoreceptor-associated, GTPase-accelerating protein. This specific signaling adaptation extended to a broader loss of autoreceptor control of interneuron spiking. These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease.

Oxotremorine - pharmacology

RGS Proteins - genetics

Synaptic Transmission - physiology

Calcium Channels - metabolism

Muscarinic Agonists - pharmacology

Autoreceptors - metabolism

Cell Communication - physiology

Acetylcholine - metabolism

Receptors, Dopamine D2 - metabolism

Corpus Striatum - cytology

Corpus Striatum - metabolism

Up-Regulation - physiology

Receptors, Dopamine D2 - drug effects

RGS Proteins - metabolism

Synaptic Transmission - drug effects

Parkinson Disease - metabolism

Action Potentials - drug effects

Dopamine - metabolism

Calcium Channels - drug effects

Mice, Inbred C57BL

Interneurons - drug effects

Rats

Mice, Transgenic

Receptor, Muscarinic M4 - metabolism

Down-Regulation - drug effects

Parkinson Disease - physiopathology

Autoreceptors - drug effects

Action Potentials - physiology

Down-Regulation - physiology

Up-Regulation - drug effects

Animals

Interneurons - metabolism

Signal Transduction - drug effects

Receptor, Muscarinic M4 - drug effects

Cell Communication - drug effects

Corpus Striatum - drug effects

Signal Transduction - physiology

Mice

Details

Title: Subtitle: RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion
Creators: Jun Ding - Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, USA
Jaime N Guzman
Tatiana Tkatch
Songhai Chen
Joshua A Goldberg
Philip J Ebert
Pat Levitt
Charles J Wilson
Heidi E Hamm
D James Surmeier
Resource Type: Journal article
Publication Details: Nature neuroscience, Vol.9(6), pp.832-842
Publisher: United States
DOI: 10.1038/nn1700
PMID: 16699510
ISSN: 1097-6256
eISSN: 1546-1726
Grant note: 32 NS 050900 / NINDS NIH HHS NS 37760 / NINDS NIH HHS MH45156 / NIMH NIH HHS HD15052 / NICHD NIH HHS NS 34696 / NINDS NIH HHS T32 MH065215 / NIMH NIH HHS MH065215 / NIMH NIH HHS
Language: English
Date published: 06/2006
Academic Unit: Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040257702771

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