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| [PMID]: | 17332265 |
| [Au] Autor: | Preuss H; Ghorai P; Kraus A; Dove S; Buschauer A; Seifert R |
| [Ad] Endereço: | Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany. |
| [Ti] Título: | Constitutive activity and ligand selectivity of human, guinea pig, rat, and canine histamine H2 receptors. |
| [So] Source: | J Pharmacol Exp Ther;321(3):983-95, 2007 Jun. | | [Is] ISSN: | 0022-3565 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | Previous studies revealed pharmacological differences between human and guinea pig histamine H(2) receptors (H(2)Rs) with respect to the interaction with guanidine-type agonists. Because H(2)R species variants are structurally very similar, comparative studies are suited to relate different properties of H(2)R species isoforms to few molecular determinants. Therefore, we systematically compared H(2)Rs of human (h), guinea pig (gp), rat (r), and canine (c). Fusion proteins of hH(2)R, gpH(2)R, rH(2)R, and cH(2)R, respectively, and the short splice variant of G(salpha), G(salphaS), were expressed in Sf9 insect cells. In the membrane steady-state GTPase activity assay, cH(2)R-G(salphaS) but neither gpH(2)R-G(salphaS) nor rH(2)R-G(salphaS) showed the hallmarks of increased constitutive activity compared with hH(2)R-G(salphaS), i.e., increased efficacies of partial agonists, increased potencies of agonists with the extent of potency increase being correlated with the corresponding efficacies at hH(2)R-G(salphaS), increased inverse agonist efficacies, and decreased potencies of antagonists. Furthermore, in membranes expressing nonfused H(2)Rs without or together with mammalian G(salphaS) or H(2)R-G(salpha) fusion proteins, the highest basal and GTP-dependent increases in adenylyl cyclase activity were observed for cH(2)R. An example of ligand selectivity is given by metiamide, acting as an inverse agonist at hH(2)R-G(salphaS), gpH(2)R-G(salphaS), and rH(2)R-G(salphaS) in the GTPase assay in contrast to being a weak partial agonist with decreased potency at cH(2)R-G(salphaS). In conclusion, the cH(2)R exhibits increased constitutive activity compared with hH(2)R, gpH(2)R, and rH(2)R, and there is evidence for ligand-specific conformations in H(2)R species isoforms. |
| [Mh] Termos MeSH primário: |
Agonistas dos Receptores Histamínicos/farmacologia
Antagonistas dos Receptores Histamínicos H2/farmacologia
Receptores Histamínicos H2/metabolismo
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| [Mh] Termos MeSH secundário: |
Adenilil Ciclases/metabolismo
Animais
Baculoviridae/genética
Linhagem Celular
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Cães
GTP Fosfo-Hidrolases/metabolismo
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética
Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo
Cobaias
Histamina/farmacologia
Seres Humanos
Ligantes
Metiamida/farmacologia
Ratos
Receptores Histamínicos H2/genética
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/metabolismo
Especificidade da Espécie
Spodoptera
Transfecção
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Histamine Agonists); 0 (Histamine H2 Antagonists); 0 (Ligands); 0 (Receptors, Histamine H2); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 3K7670861M (Metiamide); 820484N8I3 (Histamine); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gs); EC 4.6.1.1 (Adenylyl Cyclases) |
| [Em] Mês de entrada: | 0707 |
| [Cu] Atualização por classe: | 151119 |
[Lr] Data última revisão:
| 151119 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 070303 |
| [St] Status: | MEDLINE |
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