Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopamine D3 receptor pharmacology differs from that of the dopamine D2 receptor despite a high degree of receptor sequence similarity. The greatest divergence of the primary sequences of D3 and D2 receptors occurs in the predicted third intracellular loops of the receptors, a region implicated in G protein binding and function. To determine whether this domain specifies the distinct ligand binding and signal transduction characteristics of the D3 receptor, we developed a chimeric receptor, replacing the third intracellular loop of the human D3 receptor with the third intracellular loop of the human D2 receptor. The pharmacology of the chimeric receptor expressed in Chinese hamster ovary cells was examined and compared with that of human dopamine D2 and D3 receptors expressed in the same cell line. The chimeric receptor retained characteristic human D3 receptor binding; the D2 third intracellular loop present in the chimeric receptor did not reduce high affinity agonist binding, characteristic of the D3 receptor, or make high affinity sites sensitive to GTP analogs. Unlike the native human D3 receptor, the chimeric receptor was negatively coupled to adenylyl cyclase through a pertussis toxin-sensitive pathway, apparently mediated by the D2 third intracellular loop. The ability of D3 ligand binding domains to produce a D2 functional response implies that the third intracellular loop of the D3 receptor is unable to mediate this D2 response in Chinese hamster ovary cells. The inhibition of adenylyl cyclase seen with the chimeric receptor is less than the inhibition produced by D2 receptor coupling, suggesting that additional sequences in the D2 receptor contribute to normal G protein coupling.
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PMID:Characterization of a chimeric human dopamine D3/D2 receptor functionally coupled to adenylyl cyclase in Chinese hamster ovary cells. 765 68

Transfection of a human dopamine D3 receptor cDNA in a neuroblastoma-glioma hybrid cell line (NG 108-15) provided clonal cell lines stably expressing up to 600 fmol per mg protein of [125I]iodosulpiride binding sites. Dopamine and several agonists distinguished two receptor-affinity states in membranes. In the case of dopamine, the high-affinity state (Ki = 0.9 nM, 30% of total binding) was completely converted into a low-affinity state (Ki = 57 nM) in the presence of 10 microM guanosine-5'-O-(3-thiotriphosphate). In addition to these two sites, a site with a very low affinity for dopamine was evidenced in whole cells. The dopamine D3 receptor mediated two responses: c-fos activation, as measured by the appearance of Fos-like immunoreactivity, and increased mitogenesis, as measured by incorporation of [3H]thymidine. The Fos-like immunoreactivity appeared within 30 min, lasted 2 h and was blocked by the partially selective dopamine D3 receptor compound (+)-UH 232 (cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin). The mitogenic effect, which occurred after a lag time (over 2 h stimulation), was produced with subnanomolar potency and full intrinsic activity by several compounds previously identified as dopamine D2 receptor agonists, e.g. quinpirole, (+)-7-OH-DPAT ((+)-7-hydroxy-2-(di-n-propylamino)tetralin) and RU 24926 (N-n-propyl-di-beta(3-hydroxyphenyl)-ethylamine), and was reversibly blocked by (+)-UH 232 (Ki = 9 nM). Talipexole (B-HT 920, 5-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin) was identified as a partial agonist at the dopamine D3 receptor. Dopamine D3 receptor-mediated mitogenesis was potentiated by a phorbol ester and was abolished by pretreatment with pertussis toxin. A mitogenic effect of same amplitude was elicited by bradykinin or carbachol, both acting through constitutive receptors. Bradykinin markedly activated inositol phosphate turnover, and had no effect on forskolin-stimulated cyclic AMP accumulation. Carbachol inhibited forskolin-stimulated cyclic AMP accumulation and had no effect on inositol-phosphate turnover. Quinpirole had no effect on any of these second messenger pathways. Thus, in transfected NG 108-15 cells, the dopamine D3 receptor is coupled to a pertussis toxin-sensitive G protein and mediates two possibly unrelated biological effects, through initial biochemical events that remain to be identified.
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PMID:Functional coupling of the human dopamine D3 receptor in a transfected NG 108-15 neuroblastoma-glioma hybrid cell line. 795 35