RGS9-2 modulates D2 dopamine receptor-mediated Ca2+ channel inhibition in rat striatal cholinergic interneurons.
Regulator of G protein signaling (RGS) proteins negatively regulate receptor-mediated second messenger responses by enhancing the GTPase activity of Galpha subunits. We describe a receptor-specific role for an RGS protein at the level of an individual brain neuron. RGS9-2 and Gbeta(5) mRNA and protein complexes were detected in striatal cholinergic and gamma-aminobutyric acidergic neurons. Dialysis of cholinergic neurons with RGS9 constructs enhanced basal Ca(2+) channel currents and reduced D(2) dopamine receptor modulation of Cav2.2 channels. These constructs did not alter M(2) muscarinic receptor modulation of Cav2.2 currents in the same neuron. The noncatalytic DEP-GGL domain of RGS9 antagonized endogenous RGS9-2 activity, enhancing D(2) receptor modulation of Ca(2+) currents. In vitro, RGS9 constructs accelerated GTPase activity, in agreement with electrophysiological measurements, and did so more effectively at Go than Gi. These results implicate RGS9-2 as a specific regulator of dopamine receptor-mediated signaling in the striatum and identify a role for GAP activity modulation by the DEP-GGL domain.
Cabrera-Vera
Theresa M
TM
Institute for Neuroscience and Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Hernandez
Salvador
S
Earls
Laurie R
LR
Medkova
Martina
M
Sundgren-Andersson
Anna K
AK
Surmeier
D James
DJ
Hamm
Heidi E
HE
D000818:Animals; D001483:Base Sequence; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020710:RGS Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D015220:Calcium Channels; D044387:GTP-Binding Protein beta Subunits; C490610:Gnb5 protein, rat; D020710:RGS Proteins; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; C116925:regulator of g-protein signaling 9; D004247:DNA