title: Prostaglandin E2 acts on EP1 receptor and amplifies both dopamine D1 and D2 receptor signaling in the striatum.
abstract: Dopamine is involved in multiple neural functions including motor control, reward and motivational processing, learning and reinforcement, and cognitive attention. Dopamine binds to two distinct classes of receptors, namely D1 and D2, to exert these functions. Various endogenous substances regulate dopamine signaling, although their physiological functions are not fully understood. Here, we examined the role of prostaglandin E2 (PGE2) and one of its receptors, EP1, in dopaminergic function in the striatum. EP1 was expressed in both preprodynorphin-containing D1 and preproenkephalin-containing D2 neurons, and PGE2 was produced in striatal slices in response to both D1 and D2 dopamine receptor stimulation. EP1-deficient mice exhibited significant suppression of hyperlocomotion induced by cocaine or SKF81297 (6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine hydrobromide), a D1 agonist, and significant attenuation of catalepsy induced by raclopride, a D2 antagonist. Despite these behavioral defects, the extracellular concentration of dopamine was not suppressed in the striatum of EP1-deficient mice, and the densities of D1 and D2 receptors in the striatum were not different between the two genotypes. Stimulation of the D1 receptor induced phosphorylation of dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34 in striatal slices, and the addition of indomethacin, a PG synthesis inhibitor, attenuated the D1 agonist-induced increase in DARPP-32-Thr34 phosphorylation. The further addition of an EP1 agonist restored the indomethacin-attenuated phosphorylation. Furthermore, both D1- and D2-mediated changes in the DARPP-32-Thr34 phosphorylation were attenuated in EP1-/- slices. These results suggest that PGE2 is formed in response to dopamine receptor stimulation in the striatum and amplifies both D1 and D2 receptor signaling via EP1.
authors.affiliation: Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Kitaoka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Furuyashiki
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
authors.forename: Takahide
authors.initials: T
authors.lastname: Shuto
authors.forename: Sho
authors.initials: S
authors.lastname: Koyasu
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017447:Receptors, Dopamine D1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D058306:Receptors, Prostaglandin E, EP1 Subtype; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: C545636:Ptger1 protein, mouse; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D003042:Cocaine; D015232:Dinoprostone