DRD3 Membrane Protein Introduction

Introduction of DRD3

DRD3 is a member of the dopamine receptor family, which is classified into two groups: the D1-like receptor class containing DRD1 and DRD5 and the D2-like receptor class containing DRD3, DRD3, and DRD4. DRD3 has the highest affinity for dopamine. DRD3 is a G-protein coupled receptor that inhibits adenylyl cyclase activity. Its signaling pathway is primarily mediated by interaction with and activation of heterotrimeric GTP-binding proteins (G proteins). GPCRs control pro-survival signaling pathways (e.g. ERK and Akt) that are broadly important in human cancer.

Function of DRD3 Membrane Protein

DRD3 is located in the brain areas that control motor function, and DRD3 antagonism has been shown to exacerbate locomotor activity in the brain. In addition, antipsychotics with comparatively low DRD3 affinity, such as clozapine, are reported to cause significantly rarer movement disorders. The DRD3 gene has been suggested as a susceptibility factor for TD, and the Ser9Gly SNP of this gene has been investigated extensively, resulting in many positive findings. Dopamine functions as regulation of movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. DRD3 is overexpressed by several types of human cancer and its inhibition is associated with anti-cancer activity.

Fig.1 Structure of DRD3 membrane protein.

Application of DRD3 Membrane Protein in Literature

1. Kiss B., et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010, 333(1): 328-40. PubMed ID: 20093397
   
   

   This article reports that the antagonist-partial agonist properties of cariprazine at D(3) and D(2) receptors, with very high and preferential affinity to D(3) receptors, making it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics.

2. Chien E.Y., et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science. 2010, 330: 1091-1095. PubMed ID: 21097933
   
   

   This article reveals that the difference between the highly homologous D2R and D3R for an extracellular extension of the eticlopride binding site consisting of a second binding pocket for the aryl amide of R-22.

3. Slot, L. A. B., et al. Action of novel antipsychotics at human dopamine D₃ receptors coupled to G protein and ERK1/2 activation. Neuropharmacology. 2007, 53(2): 232-41. PubMed ID: 17588617
   
   

   This article underlines the differences in dopamine D(3) properties of new generation antipsychotics which may need to be considered in understanding their diverse therapeutic actions.

4. Ye N., et al. Further SAR study on 11-O-substituted aporphine analogues: identification of highly potent dopamine D3 receptor ligands. Bioorg Med Chem. 2011, 9(6): 1999-2008. PubMed ID: 21334902
   
   

   This article shows a series of new aporphine analogues (aporlogues) displayed well to high affinity at the D(3) receptor, low or no affinity at the D(1) and D(2) receptors and may be useful in the treatment of several brain disorders.

5. Gerlach M., et al. Role of dopamine D₃ and serotonin 5-HT_1A receptors in L-DOPA-induced dyskinesias and effects of sarizotan in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease. J Neural Transm (Vienna). 2011, 118(12): 1733-42. PubMed ID: 21253782
   
   

   This article identifies that D(3) receptors are involved in the action of sarizotan, which is in contrast to the more general involvement of 5-HT(1A) receptors in the anti-dyskinetic effects of sarizotan.

DRD3 Preparation Options

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