Distinct functions of the two isoforms of dopamine D2 receptors
Abstract
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.
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- Authors
- Usiello, A., Baik, J.-H., Rougé-Pont, F., Picetti, R., Dierich, A., LeMeur, M., Piazza, P. V., & Borrelli, E.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Corresponding author
- Borrelli, Emiliana
- Venue
- Nature
- Published
- 2000-11
- Volume
- 408
- Issue
- 6809
- Pages
- 199-203
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1546116904
- Cited by
- 717
- References
- 30
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 17 · 2023: 20 · 2022: 24 · 2021: 29 · 2020: 22 · 2019: 32 · 2018: 24 · 2017: 42 · 2016: 32 · 2015: 39 · 2014: 38 · 2013: 40 · 2012: 36
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- dopamine D2 receptor, alternative splicing, presynaptic autoreceptors, haloperidol, catalepsy, antipsychotic drugs, schizophrenia, dopamine D1 receptor
- MeSH terms
- Animals, Apomorphine, Benzazepines, Catalepsy, Chimera, Dopamine, Haloperidol, Mice, Inbred C57BL, Spiperone, Synapses, Signal Transduction, Mutagenesis, Receptors, Dopamine D2, Mice, Knockout, Dopamine Agonists, Dopamine Antagonists, Quinpirole, Protein Isoforms, Mice
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