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Abstract:

Accurate characterization of the molecular mechanisms of the action of ligands is an extremely important issue for their appropriate research, pharmacological, and therapeutic uses. In view of this fact, the aim of the present work was to investigate the mechanisms involved in the actions of mepyramine at the guinea pig H1 receptor stably expressed in Chinese hamster ovary cells. We found that mepyramine is able to decrease the basal constitutive activity of the guinea pig H1 receptor, to bind with high affinity to a Gq/11 protein-coupled form of the receptor and to promote a G protein-coupled inactive state of the H1 receptor that interferes with the Gq/11-mediated signaling of the endogenously expressed ATP receptor, as predicted by the Cubic Ternary Complex Model of receptor occupancy. The effect of mepyramine on ATP-induced signaling was specifically neutralized by Gα11 overexpression, indicating that mepyramine is able to reduce G protein availability for other non-related receptors associated with the same signaling pathway. Finally, we found a loss of mepyramine efficacy in decreasing basal levels of intracellular calcium at high Gα11 expression levels, which can be theoretically explained in terms of high H1 receptor constitutive activity. The whole of the present work sheds new light on H1 receptor pharmacology and the mechanisms H1 receptor inverse agonists could use to exert their observed negative efficacy.

Registro:

Documento: Artículo
Título:Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein
Autor:Fitzsimons, C.P.; Monczor, F.; Fernández, N.; Shayo, C.; Davio, C.
Filiación:Laboratorio de Radioisótopos, Fac. de Farmacia Y Bioquímica, Universidad de Buenos Aires, Buenos Aires, 1113, Argentina
Inst. de Biol. Y Med. Experimental, Fac. de Ciencias Exactas Y Naturales, Universidad de Buenos Aires, Buenos Aires, 1113, Argentina
Depto. Fisiol., Biol. Molec. Y Cel., Fac. de Ciencias Exactas Y Naturales, Universidad de Buenos Aires, Buenos Aires, 1113, Argentina
Consejo Natl. de Invest. Cie. Y Tec., Buenos Aires, 1113, Argentina
Laboratorio de Radioisótopes, Fac. de Farmacia Y Bioquímica, Universidad de Buenos Aires, Junin 956, PB, Buenos Aires 1113, Argentina
Palabras clave:Adenosinetriphosphate; Biochemistry; Calcium; Cells; Proteins; Mepyramine; Molecular mechanisms; Pharmacology; Signaling pathways; Drug products; calcium; G protein coupled receptor; histamine H1 receptor; mepyramine; purine receptor; adenosine triphosphate; calcium; guanine nucleotide binding protein; guanine nucleotide binding protein alpha subunit; guanosine 5' o (3 thiotriphosphate); histamine H1 receptor; histamine H1 receptor antagonist; inositol phosphate; ligand; triprolidine; animal cell; article; calcium blood level; Chinese hamster; CHO cell; controlled study; drug mechanism; guinea pig; molecular model; nonhuman; nucleotide sequence; priority journal; protein expression; receptor affinity; signal transduction; animal; cell membrane; chemical model; chemistry; dose response; hamster; metabolism; molecular cloning; protein binding; Western blotting; Animalia; Cavia porcellus; Cricetinae; Cricetulus griseus; Sus scrofa; Adenosine Triphosphate; Animals; Blotting, Western; Calcium; Cell Membrane; CHO Cells; Cloning, Molecular; Cricetinae; Dose-Response Relationship, Drug; GTP-Binding Protein alpha Subunits, Gq-G11; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Histamine H1 Antagonists; Inositol Phosphates; Ligands; Models, Chemical; Protein Binding; Pyrilamine; Receptors, Histamine H1; Triprolidine
Año:2004
Volumen:279
Número:33
Página de inicio:34431
Página de fin:34439
DOI: http://dx.doi.org/10.1074/jbc.M400738200
Título revista:Journal of Biological Chemistry
Título revista abreviado:J. Biol. Chem.
ISSN:00219258
CODEN:JBCHA
CAS:calcium, 7440-70-2; mepyramine, 6036-95-9, 91-84-9; adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; guanosine 5' o (3 thiotriphosphate), 37589-80-3; inositol phosphate, 15421-51-9; triprolidine, 486-12-4, 550-70-9; Adenosine Triphosphate, 56-65-5; Calcium, 7440-70-2; GTP-Binding Protein alpha Subunits, Gq-G11, EC 3.6.1.46; GTP-Binding Proteins, EC 3.6.1.-; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Histamine H1 Antagonists; Inositol Phosphates; Ligands; Pyrilamine, 91-84-9; Receptors, Histamine H1; Triprolidine, 486-12-4
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_00219258_v279_n33_p34431_Fitzsimons.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v279_n33_p34431_Fitzsimons

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Citas:

---------- APA ----------
Fitzsimons, C.P., Monczor, F., Fernández, N., Shayo, C. & Davio, C. (2004) . Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein. Journal of Biological Chemistry, 279(33), 34431-34439.
http://dx.doi.org/10.1074/jbc.M400738200
---------- CHICAGO ----------
Fitzsimons, C.P., Monczor, F., Fernández, N., Shayo, C., Davio, C. "Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein" . Journal of Biological Chemistry 279, no. 33 (2004) : 34431-34439.
http://dx.doi.org/10.1074/jbc.M400738200
---------- MLA ----------
Fitzsimons, C.P., Monczor, F., Fernández, N., Shayo, C., Davio, C. "Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein" . Journal of Biological Chemistry, vol. 279, no. 33, 2004, pp. 34431-34439.
http://dx.doi.org/10.1074/jbc.M400738200
---------- VANCOUVER ----------
Fitzsimons, C.P., Monczor, F., Fernández, N., Shayo, C., Davio, C. Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein. J. Biol. Chem. 2004;279(33):34431-34439.
http://dx.doi.org/10.1074/jbc.M400738200