Identification and characterization of novel properties of the human D3 dopamine receptor.
Among dopamine receptors, the function and properties of the D3 receptor subtype are poorly understood. Here we report the identification and characterization of two unique properties of the human D3 receptor. The D3 receptor exhibits a tolerance property wherein the magnitude of the second agonist-induced response is reduced by 60% compared to the first response and progressively decreases upon repeated agonist application. In addition, unlike the D2 dopamine receptor, the D3 receptor response terminates 15-fold more slowly upon agonist removal. Using D3/D2S chimeric receptors, we demonstrate that D3 receptor tolerance property is mediated by a novel conformational mechanism involving the D3 receptor second cytoplasmic region. The slow response termination rate property requires the third cytoplasmic region and is due to the high affinity of the D3 receptor for ligand as well as its unique G-protein signaling mechanism.
Kuzhikandathil
Eldo V
EV
Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA. kuzhikev@umdnj.edu
Westrich
Ligia
L
Bakhos
Samer
S
Pasuit
Jennifer
J
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004361:Drug Tolerance / Q000502:physiology; D006801:Humans; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D050637:Receptors, Dopamine D3; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
C493593:DRD3 protein, human; D018491:Dopamine Agonists; C493594:Drd3 protein, mouse; D008024:Ligands; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; C113776:dopamine D2L receptor; D004298:Dopamine