Neurotensin regulates DARPP‐32 Thr34 phosphorylation in neostriatal neurons by activation of dopamine D1‐type receptors

• Published in: Journal of neurochemistry Vol. 81; no. 2; pp. 325 - 334
• Main Authors: Matsuyama, Seiichiro, Higashi, Hideho, Maeda, Hisao, Greengard, Paul, Nishi, Akinori
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.04.2002; Blackwell
• Subjects: Animals; Biological and medical sciences; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Cobalt - pharmacology; DARPP‐32; dopamine; Dopamine - physiology; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Antagonists - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Fundamental and applied biological sciences. Psychology; glutamate; Glutamine - physiology; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; neostriatum; Neostriatum - cytology; Neostriatum - metabolism; Nerve Tissue Proteins; Neurons - metabolism; neurotensin; Neurotensin - antagonists & inhibitors; Neurotensin - pharmacology; Neurotensin - physiology; Phosphoproteins - deficiency; Phosphoproteins - genetics; Phosphoproteins - metabolism; phosphorylation; Phosphorylation - drug effects; Piperidines - pharmacology; Pyrazoles - pharmacology; Quinolines - pharmacology; Receptors, Dopamine D1 - antagonists & inhibitors; Receptors, Dopamine D1 - metabolism; Receptors, Neurotensin - antagonists & inhibitors; Signal Transduction - drug effects; Signal Transduction - physiology; Tetrodotoxin - pharmacology; Vertebrates: nervous system and sense organs; Phosphorylation; Dopamine; Rodentia; Central nervous system; D1 Dopamine receptor; Basal ganglion; Corpus striatum; Glutamate receptor; Neurotensin; Catecholamine; Glutamate; Neuropeptide; Neuromodulation; Neurotensin receptor; Signal transduction; Vertebrata; Mammalia; Mouse; Neurotransmitter; DARPP-32 protein; Dopaminergic neuron; Brain (vertebrata)
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2002.00822.x

Neurotensin modulates dopaminergic transmission in the nigrostriatal system. DARPP‐32, a dopamine‐ and cAMP‐regulated phosphoprotein of Mr 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 K0.5 of ∼50 nm. 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.