The D3 receptor belongs to the D2-like receptor subfamily, which also includesD2 andD4 receptors. It couples primarily toGi/Go proteins, leading to inhibition ofadenylyl cyclase and reduced intracellularcAMP levels.[7]
The D3 receptor displays the highest binding affinity for dopamine among dopamine receptor subtypes, making it a key regulator of tonic dopamine signaling.[8]
D3 receptors are primarily expressed in limbic brain regions such as the nucleus accumbens, islands of Calleja, and olfactory tubercle. Their distribution in phylogenetically older brain areas suggests an important role in emotion, motivation, and cognition.[9]
Activation of the D3 receptor regulates dopamine release and modulates neuronal excitability. Preclinical and clinical studies implicate it in:
Parkinson's disease – D3 agonists such aspramipexole androtigotine show neuroprotective effects, reducealpha-synuclein aggregation, and improve motor and non-motor symptoms.[10]
Neuropsychiatric disorders – Altered DRD3 signaling has been associated withschizophrenia,bipolar disorder, andmajor depression. Some D3 ligands exert antidepressant-like effects in animal models.[11]
Addiction – D3 receptors modulate reward pathways; antagonists such asSB-277011-A show promise in reducing drug-seeking behavior in preclinical models.[12]
Therapeutic target – Due to its role in motor control, motivation, and reward, DRD3 is a therapeutic target for Parkinson's disease, schizophrenia, and substance use disorders.
Drug design – High selectivity ligands for D3 are actively pursued to minimize side effects associated with D2 receptor blockade.
Biomarker potential – Polymorphisms in DRD3 are under investigation as genetic biomarkers for treatment response and psychiatric vulnerability.
^Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (January 1998). "Dopamine receptors: from structure to function".Physiological Reviews.78 (1):189–225.doi:10.1152/physrev.1998.78.1.189.PMID9457173.
^Robinson SW, Jarvie KR, Caron MG (August 1994). "High affinity agonist binding to the dopamine D3 receptor: chimeric receptors delineate a role for intracellular domains".Molecular Pharmacology.46 (2):352–356.doi:10.1016/S0026-895X(25)09690-7.PMID7915820.
^Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (September 1990). "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics".Nature.347 (6289):146–151.doi:10.1038/347146a0.PMID1975644.
^Breuer ME, Groenink L, Oosting RS, Buerger E, Korte M, Ferger B, et al. (August 2009). "Antidepressant effects of pramipexole, a dopamine D3/D2 receptor agonist, and 7-OH-DPAT, a dopamine D3 receptor agonist, in olfactory bulbectomized rats".European Journal of Pharmacology.616 (1–3):134–140.doi:10.1016/j.ejphar.2009.06.029.PMID19549514.
^Krishnamoorthy S, Rajan R, Banerjee M, Kumar H, Sarma G, Krishnan S, et al. (September 2016). "Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson's disease patients".Parkinsonism & Related Disorders.30:13–17.doi:10.1016/j.parkreldis.2016.06.005.PMID27325396.
^Griffon N, Jeanneteau F, Prieur F, Diaz J, Sokoloff P (September 2003). "CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors".Brain Research. Molecular Brain Research.117 (1):47–57.doi:10.1016/S0169-328X(03)00283-3.PMID14499480.
^Binda AV, Kabbani N, Lin R, Levenson R (September 2002). "D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N".Molecular Pharmacology.62 (3):507–513.doi:10.1124/mol.62.3.507.PMID12181426.
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