Most central nervous system D2 dopamine receptors are coupled to their effectors by Go.
We reported previously that Go-deficient mice develop severe neurological defects that include hyperalgesia, a generalized tremor, lack of coordination, and a turning syndrome somewhat reminiscent of unilateral lesions of the dopaminergic nigro-striatal pathway. By using frozen coronal sections of serially sectioned brains of normal and Go-deficient mice, we studied the ability of several G protein coupled receptors to promote binding of GTPgammaS to G proteins and the ability of GTP to promote a shift in the affinity of D2 dopamine receptor for its physiologic agonist dopamine. We found a generalized, but not abolished reduction in agonist-stimulated binding of GTPgammaS to frozen brain sections, with no significant left-right differences. Unexpectedly, the ability of GTP to regulate the binding affinity of dopamine to D2 receptors (as seen in in situ [(35)S]sulpiride displacement curves) that was robust in control mice, was absent in Go-deficient mice. The data suggest that most of the effects of the Gi/Go-coupled D2 receptors in the central nervous system are mediated by Go instead of Gi1, Gi2, or Gi3. In agreement with this, the effect of GTP on dopamine binding to D2 receptors in double Gi1 plus Gi2- and Gi1 plus Gi3-deficient mice was essentially unaffected.
Department of Anesthesiology, University of California, Los Angeles, CA 90095-7115, USA.
M
M
Jiang
K
K
Spicher
G
G
Boulay
Y
Y
Wang
L
L
Birnbaumer
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D065127:Dopamine D2 Receptor Antagonists; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000819:agonists / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000494:pharmacology
D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; C045105:iodosulpride; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013469:Sulpiride; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins