RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion.
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.
Ding
Jun
J
Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, USA.
Guzman
Jaime N
JN
Tkatch
Tatiana
T
Chen
Songhai
S
Goldberg
Joshua A
JA
Ebert
Philip J
PJ
Levitt
Pat
P
Wilson
Charles J
CJ
Hamm
Heidi E
HE
Surmeier
D James
DJ
D000109:Acetylcholine / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017660:Autoreceptors / Q000187:drug effects / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018721:Muscarinic Agonists / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D043588:Receptor, Muscarinic M4 / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D017660:Autoreceptors; D015220:Calcium Channels; D018721:Muscarinic Agonists; D020710:RGS Proteins; D043588:Receptor, Muscarinic M4; D017448:Receptors, Dopamine D2; C098799:RGS4 protein; D010095:Oxotremorine; D000109:Acetylcholine; D004298:Dopamine