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Distinct functions of the two isoforms of dopamine D2 receptors

Author

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  • Alessandro Usiello

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP)

  • Ja-Hyun Baik

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP)

  • Françoise Rougé-Pont

    (INSERM U259, Université V. Segalen Bordeaux 2)

  • Roberto Picetti

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP)

  • Andrée Dierich

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP)

  • Marianne LeMeur

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP)

  • Pier Vincenzo Piazza

    (INSERM U259, Université V. Segalen Bordeaux 2)

  • Emiliana Borrelli

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP)

Abstract

Signalling through dopamine D2 receptors governs physiological functions related to locomotion, hormone production and drug abuse1,2,3,4,5,6,7. D2 receptors are also known targets of antipsychotic drugs that are used to treat neuropsychiatric disorders such as schizophrenia8. By a mechanism of alternative splicing, the D2 receptor gene encodes two molecularly distinct isoforms9, 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 haloperidol1 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.

Suggested Citation

  • Alessandro Usiello & Ja-Hyun Baik & Françoise Rougé-Pont & Roberto Picetti & Andrée Dierich & Marianne LeMeur & Pier Vincenzo Piazza & Emiliana Borrelli, 2000. "Distinct functions of the two isoforms of dopamine D2 receptors," Nature, Nature, vol. 408(6809), pages 199-203, November.
    • Handle: RePEc:nat:nature:v:408:y:2000:i:6809:d:10.1038_35041572
    DOI: 10.1038/35041572
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    Cited by:

    1. Leonardo Sportelli & Daniel P. Eisenberg & Roberta Passiatore & Enrico D’Ambrosio & Linda A. Antonucci & Jasmine S. Bettina & Qiang Chen & Aaron L. Goldman & Michael D. Gregory & Kira Griffiths & Thom, 2024. "Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Toshikazu Sasabe & Shoichi Ishiura, 2010. "Alcoholism and Alternative Splicing of Candidate Genes," IJERPH, MDPI, vol. 7(4), pages 1-19, March.
    3. Ya-Qiang Zhang & Wei-Peng Lin & Li-Ping Huang & Bing Zhao & Cheng-Cheng Zhang & Dong-Min Yin, 2021. "Dopamine D2 receptor regulates cortical synaptic pruning in rodents," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Katarzyna Świtała & Aleksandra Bojarczuk & Jacek Hajto & Marcin Piechota & Maciej Buryta & Agata Leońska-Duniec, 2022. "Impact of the DRD2 Polymorphisms on the Effectiveness of the Training Program," IJERPH, MDPI, vol. 19(9), pages 1-14, April.
    5. Alessandro Bertolino & Paolo Taurisano & Nicola Marco Pisciotta & Giuseppe Blasi & Leonardo Fazio & Raffaella Romano & Barbara Gelao & Luciana Lo Bianco & Madia Lozupone & Annabella Di Giorgio & Grazi, 2010. "Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance," PLOS ONE, Public Library of Science, vol. 5(2), pages 1-10, February.
    6. Agnieszka Boroń & Małgorzata Śmiarowska & Anna Grzywacz & Krzysztof Chmielowiec & Jolanta Chmielowiec & Jolanta Masiak & Tomasz Pawłowski & Dariusz Larysz & Andrzej Ciechanowicz, 2022. "Association of Polymorphism within the Putative miRNA Target Site in the 3′UTR Region of the DRD2 Gene with Neuroticism in Patients with Substance Use Disorder," IJERPH, MDPI, vol. 19(16), pages 1-21, August.

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