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Neurotensin regulates DARPP‐32 Thr34 phosphorylation in neostriatal neurons by activation of dopamine D1‐type receptors
Author(s) -
Matsuyama Seiichiro,
Higashi Hideho,
Maeda Hisao,
Greengard Paul,
Nishi Akinori
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.00822.x
Subject(s) - dopaminergic , neurotensin , dopamine , neurotensin receptor , ampa receptor , endocrinology , medicine , chemistry , dopamine receptor , dopamine receptor d1 , cnqx , biology , receptor , glutamate receptor , neuropeptide , biochemistry
Neurotensin modulates dopaminergic transmission in the nigrostriatal system. DARPP‐32, a dopamine‐ and cAMP‐regulated phosphoprotein of M r 32 kDa, is phosphorylated on Thr34 by cAMP‐dependent protein kinase, resulting in its conversion into a potent inhibitor of protein phosphatase‐1 (PP 1). Here, we examined the effect of neurotensin on DARPP‐32 Thr34 phosphorylation using mouse neostriatal slices. Neurotensin stimulated DARPP‐32 Thr34 phosphorylation by 4–7‐fold with a K 0.5 of ∼50 n m . The effect of neurotensin was antagonized by a combined neurotensin receptor type‐1 (NTR1)/type‐2 (NTR2) antagonist, SR142948. It was not antagonized by a NTR1 antagonist, SR48692 or by a NTR2 antagonist, levocabastine; neither was it antagonized by the two combined. Pretreatment with TTX or cobalt abolished the effect of neurotensin. The effect of neurotensin was antagonized by a dopamine D1 antagonist, SCH23390, and by ionotropic glutamate receptor antagonists, MK801 and CNQX. These results indicate that neurotensin stimulates the release of dopamine from nigrostriatal presynaptic terminals in an NMDA receptor‐ and AMPA receptor‐dependent manner, leading to the increase in DARPP‐32 Thr34 phosphorylation. Neurotensin stimulated the phosphorylation of Ser845 of the AMPA receptor GluR1 subunit in wild‐type mice but not in DARPP‐32 knockout mice. Thus, neurotensin, by stimulating the release of dopamine, activates the dopamine D1‐receptor/cAMP/PKA/DARPP‐32/PP 1 cascade.