中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (7): 1406-1408.doi: 10.4103/1673-5374.300988

• 观点:退行性病与再生 • 上一篇    下一篇

运动障碍中的多巴胺能-胆碱能失衡:新型纹状体多巴胺D2-毒蕈碱乙酰胆碱M1受体异聚体的作用

  

  • 出版日期:2021-07-15 发布日期:2021-01-07

Dopaminergic-cholinergic imbalance in movement disorders: a role for the novel striatal dopamine D2- muscarinic acetylcholine M1 receptor heteromer

René A. J. Crans, Francisco Ciruela*   

  1. Laboratory of Toxicology, Department of Bioanalysis, Ghent University, Ghent, Belgium (Crans RAJ)
    Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain (Crans RAJ, Ciruela F)
    Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain (Ciruela F)
  • Online:2021-07-15 Published:2021-01-07
  • Contact: Francisco Ciruela, PhD,fciruela@ub.edu.
  • Supported by:
    This work was supported by the Fonds Wetenschappelijk Onderzoek (FWO-SBO, Grant number 140028), Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación/FEDER (Grant number SAF2017-87349-R), Generalitat de Catalunya (Grant numbers 2017SGR1604 and 2017SGR595) and Fundació la Marató de TV3 (grant number 20152031). Moreover, RAJC was supported by an FWO Travel Grant for a Long Stay Abroad (grant number V420718N) and an EMBO Short-Term Fellowship (grant number 6735). 

摘要: https://orcid.org/0000-0003-0832-3739 
(Francisco Ciruela)

Abstract: The striatum is the primary input structure of the basal ganglia, which participates in motivational and goal-directed behaviors (Pisani et al., 2007). In physiological conditions, local cholinergic interneurons (ChIs) and dopaminergic afferents modulate basal ganglia output through striatal projection neurons, also called medium spiny neurons (MSNs). In general, the release of the neurotransmitters dopamine (DA) and acetylcholine (ACh) elicits contradictory effects on MSNs, which express their corresponding DA receptors (DARs) and muscarinic acetylcholine receptors (mAChRs), respectively (Ztaou and Amalric, 2019). Recently, we discovered a novel receptor-receptor interaction (i.e., heteromerization) between the dopamine D2 receptor (D2R) and the muscarinic acetylcholine M1 receptor (M1R), both expressed at striatopallidal MSNs (Crans et al., 2020). The putative striatal D2R-M1R complex coordinates a sophisticated interplay between the dopaminergic and cholinergic neurotransmission systems. Fuxe et al. (2012) foresaw that the existence of this heteromer within the striatum would mechanistically justify the use of anticholinergics in Parkinson’s disease (PD) treatment, thus opening up the development of novel pharmacotherapeutic strategies for PD management. As a proof of concept, we demonstrated that an M1R-selective antagonist (i.e., VU0255035, 10 mg/kg, i.p.) potentiated the antiparkinsonian-like efficacy of an ineffective D2R-selective agonist dose (i.e., sumanirole, 3 mg/kg, i.p.) in a rodent model of experimental Parkinsonism (Crans et al., 2020). Overall, the novel D2R-M1R heteromer could serve as a specific drug target to alleviate motor deficits in PD, whereas it may avoid major adverse effects associated with traditional pharmacotherapies.