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)

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

Neurotransmitter receptors are known to have direct roles in the modulation of neuronal morphogenesis. Previous work showed that clonal mesencephalic MN9D cells individually transfected with D2-like dopamine receptors show increased neurite outgrowth following long-term exposure to the D2-like receptor agonist quinpirole. In the current study, brief stimulation of D3 receptor-expressing cells also elicited increased neurite outgrowth, which could be mimicked by the Gi/G(o) protein activator mastoparan. Pretreatment with the Gi/G(o) protein inhibitor pertussis-toxin blocked the quinpirole- and mastoparan-mediated increases in outgrowth. These results suggest that dopamine D3 receptor stimulation has an immediate, G-protein-mediated role in neuronal morphogenesis.
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PMID:PTX-sensitive regulation of neurite outgrowth by the dopamine D3 receptor. 873 Aug 32

Despite a great deal of research, the second messenger coupling of the dopamine D3 receptor has not yet been clearly established. The closely related D2 and D4 receptors have been shown to inhibit adenylyl cyclase activity in a variety of cell types, but the D3 receptor has little or no effect on this second messenger system. We now demonstrate that when the D3 receptor and adenylyl cyclase type V are coexpressed in 293 cells, the agonist quinpirole causes 70% inhibition of forskolin-stimulated cAMP levels. This effect seems to be selective for this adenylyl cyclase isoform because the D3 receptor does not inhibit adenylyl cyclase types I or VI and only weakly stimulates adenylyl cyclase type II. In contrast, the D2 receptor inhibits cAMP accumulation in 293 cells in the absence of cotransfected adenylyl cyclases and stimulates adenylyl cyclase type II to a greater extent than the D3 receptor. The inhibition of adenylyl cyclase type V by the D3 receptor is sensitive to pertussis toxin, suggesting the involvement of G proteins of the Gi family. Guanosine-5'-O-(3-thio)triphosphate binding studies indicate that the D3 receptor weakly activates all three Gialpha subunits, whereas the D2 receptor activates these G proteins to a substantially greater extent. However, despite its relative inability to promote G protein activation, the D3 receptor is capable of substantial and consistent inhibition of adenylyl cyclase type V. The robust second messenger coupling of the D3 receptor in a heterologous system with defined components provides a system for further studies of the function of this receptor and should facilitate the development and characterization of new D3 receptor ligands.
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PMID:Selective inhibition of adenylyl cyclase type V by the dopamine D3 receptor. 928 14

In this study, the ligand-receptor-G protein interactions of the dopamine D3 receptor expressed in Chinese hamster ovary cells were investigated using guanosine 5'-[gamma-thio]triphosphate-[35S] ([35S]GTPgammaS) and receptor binding experiments. Dopamine stimulated the [35S]GTPgammaS binding in a guanine nucleotide, magnesium and sodium-dependent manner. Dopamine and quinpirole produced maximal stimulation of the [35S]GTPgammaS binding whereas (+)-7-OH-DPAT and (-)-3-PPP were partial agonists. Interestingly, several compounds previously classified as D2 receptor antagonists behaved as inverse agonists at the D3 receptor, i.e., they inhibited the basal [35S]GTPgammaS binding in a dose dependent fashion. Haloperidol, (+)-UH-232, (+)-AJ-76 and raclopride were full inverse agonists but clozapine was a partial inverse agonist. Pertussis toxin treatment abolished the D3 receptor-mediated agonist as well as inverse agonist responses, indicating the involvement of Gi/Go proteins in both processes. According to the ternary complex model, agonists should bind with higher affinity to the G protein coupled receptor (RG) and thereby shift the equilibrium from free receptor (R) toward RG, which produces a biological response. However, an inverse agonist should bind with higher affinity to R than to RG and thereby inhibit the basal activity of the cell. We found that the high affinity agonist binding site (RG) was abolished by pertussis toxin treatment of the cells. However, the inverse agonists bound with the same affinity to untreated and pertussis toxin treated D3 receptor membranes. Thus, we found no evidence for the hypothesis that inverse agonists would shift the equilibrium from RG toward R by binding with higher affinity to R than to RG.
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PMID:Agonist and inverse agonist activity at the dopamine D3 receptor measured by guanosine 5'--gamma-thio-triphosphate--35S- binding. 953 1

In Chinese hamster ovary (CHO) cells transfected with the cDNA for the dopamine D3 receptor, low concentrations of dopamine (IC50: 0.5 nM) counteracted the release of arachidonic acid (AA) induced by the protein kinase C activator TPA (maximal inhibition: 15% at 10 - 30 nM). The effect of dopamine -- which was antagonized by pretreatment with pertussis toxin (PTX) or by the dopamine receptor antagonist haloperidol -- was biphasic; thus, at increasing concentrations of dopamine (100 nM - 1 microM), AA levels approached baseline. The preferential dopamine D3 receptor ligand PNU-99194A displayed an effect similar to that of dopamine; thus, whereas low concentrations of PNU-99194A (IC50: 1.9 nM) reduced TPA-induced AA release (maximal inhibition: 15% at 30 - 100 nM), higher concentrations (> or =1 microM) were ineffective. When dopamine and PNU-99194A were administered together at concentrations yielding maximal inhibition of AA release, no additive effect was observed; moreover, a high concentration of dopamine counteracted the AA-reducing effect of a low concentration of PNU-99194A and vice versa. It is suggested that D3 receptors in transfected CHO cells may exert mainly an inhibitory, but also a stimulatory influence on TPA-induced AA release, and that PNU-99194A acts as an agonist in this system.
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PMID:Both dopamine and the putative dopamine D3 receptor antagonist PNU-99194A induce a biphasic inhibition of phorbol ester-stimulated arachidonic acid release from CHO cells transfected with the dopamine D3 receptor. 1020 43

Novel signaling components of dopamine D3 receptor (D3R) were searched using yeast two-hybrid system, and the gamma subunit of elongation Factor-1B (eEF1Bgamma) was found to interact with D3R. This interaction was observed specifically between eEF1Bgamma and D3R but not with D2R or D4R. Immunocytochemical studies showed that D3R and eEF1Bgamma form clusters on the plasma membrane and their co-localization was evident in these clusters. The beta subunit of eEF1B (eEF1Bbeta), which forms a tight complex with eEF1Bgamma, was phosphorylated on serine residues in response to the stimulation of D3R. Phosphorylation of eEF1Bbeta was insensitive to pertussis toxin or wortmannin, however, stimulation of cellular protein kinase C (PKC) directly phosphorylated eEF1Bbeta and depletion of PKC abolished D3R-mediated phosphorylation of eEF1Bbeta. These results suggest the involvement of PKC, but not Gi/o proteins or phosphatidylinositol 3-kinase, in D3R-mediated phosphorylation of eEF1Bbeta. Stimulation of D3R did not activate PKC, but the activation of PKC resulted in the phosphorylation of D3R. These results show that PKC has a permissive role for the D3R-mediated phosphorylation of eEF1Bbeta, and suggest that PKC could modulate the mutual interaction between two protein by phosphorylating both D3R and eEF1Bbeta. Therefore, the cellular PKC level would be important for the D3R-mediated modulation of eEF1B, and for their cellular regulations such as protein synthesis or cellular proliferation.
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PMID:Direct and biochemical interaction between dopamine D3 receptor and elongation factor-1Bbetagamma. 1451 48