title: Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites.
abstract: Dopamine D2 receptors are highly expressed in the dorsal striatum where they participate in the regulation of (i) tyrosine hydroxylase (TH), in nigrostriatal nerve terminals, and (ii) the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), in medium spiny neurons. Two isoforms of the D2 receptor are generated by differential splicing of the same gene and are referred to as short (D2S) and long (D2L) dopamine receptors. Here we have used wild-type mice, dopamine D2 receptor knockout mice (D2 KO mice; lacking both D2S and D2L receptors) and D2L receptor-selective knockout mice (D2L KO mice) to evaluate the involvement of each isoform in the regulation of the phosphorylation of TH and DARPP-32. Incubation of striatal slices from wild-type mice with quinpirole, a dopamine D2 receptor agonist, decreased the state of phosphorylation of TH at Ser-40 and its enzymatic activity. Both effects were abolished in D2 KO mice but were still present in D2L KO mice. In wild-type mice, quinpirole inhibits the increase in DARPP-32 phosphorylation at Thr-34 induced by SKF81297, a dopamine D1 receptor agonist. This effect is absent in D2 KO as well as D2L KO mice. The inability of quinpirole to regulate DARPP-32 phosphorylation in D2L KO mice cannot be attributed to decreased coupling of D2S receptors to G proteins, because quinpirole produces a similar stimulation of [(35)S]GTPgammaS binding in wild-type and D2L KO mice. These results demonstrate that D2S and D2L receptors participate in presynaptic and postsynaptic dopaminergic transmission, respectively.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindgren
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.forename: Michel
authors.initials: M
authors.lastname: Goiny
authors.forename: John
authors.initials: J
authors.lastname: Haycock
authors.forename: Eric
authors.initials: E
authors.lastname: Erbs
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Tomas
authors.initials: T
authors.lastname: Hokfelt
authors.forename: Emiliana
authors.initials: E
authors.lastname: Borrelli
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fisone
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005260:Female; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000502:physiology; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; D019257:Quinpirole; D014446:Tyrosine 3-Monooxygenase