Distinct functions of the two isoforms of dopamine D2 receptors

• Published in: Nature (London) 2000-11, Vol.408 (6809), p.199-203
• Main Authors: Piazza, Pier Vincenzo, Dierich, Andrée, Rougé-Pont, Françoise, Borrelli, Emiliana, Baik, Ja-Hyun, Usiello, Alessandro, LeMeur, Marianne, Picetti, Roberto
• Format: Article
• Language: English
• Subjects: Animals; Apomorphine - pharmacology; Benzazepines - pharmacology; Biological and medical sciences; Catalepsy - metabolism; Cell receptors; Cell structures and functions; Cellular signal transduction; Chimera; Dopamine - metabolism; Dopamine Agonists - pharmacology; Dopamine Antagonists - pharmacology; Dopamine receptors; Drug abuse; Drug therapy; Drugs; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genetics; Haloperidol - pharmacology; Humanities and Social Sciences; letter; Life Sciences; Mental disorders; Mental illness; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); multidisciplinary; Mutagenesis; Neurology; Physiological aspects; Postsynaptic potentials; Protein Isoforms - chemistry; Protein Isoforms - physiology; Quinpirole - pharmacology; Receptors, Dopamine D2 - chemistry; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - physiology; Science; Science (multidisciplinary); Signal Transduction; Spiperone - pharmacology; Synapses - physiology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35041572

Signalling through dopamine D2 receptors governs physiological functions related to locomotion, hormone production and drug abuse. D2 receptors are also known targets of antipsychotic drugs that are used to treat neuropsychiatric disorders such as schizophrenia. By a mechanism of alternative splicing, the D2 receptor gene encodes two molecularly distinct isoforms, D2S and D2L, previously thought to have the same function. Here we show that these receptors have distinct functions in vivo; D2L acts mainly at postsynaptic sites and D2S serves presynaptic autoreceptor functions. The cataleptic effects of the widely used antipsychotic haloperidol are absent in D2L-deficient mice. This suggests that D2L is targeted by haloperidol, with implications for treatment of neuropsychiatric disorders. The absence of D2L reveals that D2S inhibits D1 receptor-mediated functions, uncovering a circuit of signalling interference between dopamine receptors.