Artículo

Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

The histamine H2 receptor (H2r) belongs to the heptahelical receptor family; upon agonist binding, members of this family activate a G protein and the downstream effector adenylyl cyclase. Like other G protein-coupled receptors, exposure of H2r to agonists produces a desensitization of the response. The present study focused on the desensitization mechanism of this receptor. Using transiently transfected COS-7 cells expressing tagged-H2r, the desensitization induced by amthamine, characterized by decreased cAMP production, was studied. Results show that the receptor was rapidly desensitized with a t1/2 = 0.49 ± 0.01 min. Because of the rapid nature of H2r desensitization, receptor phosphorylation was examined as a likely mechanism for signal attenuation. H2r desensitization was not affected by protein kinases A and C (PKA and PKC) inhibitors but was remarkably reduced by Zn2+, an inhibitor of G protein-coupled receptor kinases (GRKs). Cotransfection experiments using tagged H2r and different GRKs (2, 3, 5, or 6), demonstrated that GRK2 and GRK3 were the most potent in augmenting desensitization, causing a reduction in the maximal response to amthamine and a decrease of the t1/2 for desensitization, whereas GRK5 and GRK6 did not affect the signaling. Receptor phosphorylation correlates with desensitization for each GRK studied, whereas phosphorylation that is dependent on protein kinases A and C seemed irrelevant in receptor signal termination. These results indicate that in H2r-transfected COS-7 cells, exposure to an agonist caused desensitization controlled by H2r phosphorylation via GRK2 and GRK3.

Registro:

Documento: Artículo
Título:Histamine H2 receptor desensitization: Involvement of a select array of G protein-coupled receptor kinases
Autor:Shayo, C.; Fernandez, N.; Legnazzi, B.L.; Monczor, F.; Mladovan, A.; Baldi, A.; Davio, C.
Filiación:School of Sciences, University of Buenos Aires, Buenos Aires, Argentina
Radioisotopes Laboratory, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
Institute of Biology and Experimental Medicine, Buenos Aires, Argentina
National Research Council of Argentina, Buenos Aires, Argentina
Institute of Biology and Experimental Medicine, Obligado 2490, (1428) Buenos Aires, Argentina
Palabras clave:adenylate cyclase; amthamine; cyclic AMP; cyclic AMP dependent protein kinase; cyclic AMP dependent protein kinase inhibitor; G protein coupled receptor; G protein coupled receptor kinase; G protein coupled receptor kinase 2; G protein coupled receptor kinase 5; G protein coupled receptor kinase 6; histamine; histamine H2 receptor; protein GRK3; protein kinase C inhibitor; protein kinase inhibitor; unclassified drug; animal cell; article; controlled study; DNA transfection; enzyme active site; enzyme inhibition; enzyme kinetics; enzyme mechanism; enzyme regulation; enzyme specificity; histamine release; nonhuman; priority journal; protein phosphorylation; receptor binding; receptor down regulation; signal transduction; transcription termination
Año:2001
Volumen:60
Número:5
Página de inicio:1049
Página de fin:1056
DOI: http://dx.doi.org/10.1124/mol.60.5.1049
Título revista:Molecular Pharmacology
Título revista abreviado:Mol. Pharmacol.
ISSN:0026895X
CODEN:MOPMA
CAS:adenylate cyclase, 9012-42-4; amthamine, 142437-67-0; cyclic AMP, 60-92-4; cyclic AMP dependent protein kinase; G protein coupled receptor kinase; histamine, 51-45-6, 56-92-8, 93443-21-1
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0026895X_v60_n5_p1049_Shayo

Referencias:

  • Benovic, J.L., Strasser, R.H., Caron, M.G., Lefkowitz, Beta adrenergic receptor kinase: Identification of a novel protein kinase that phosphorylates the agonist occupied form of the receptor (1986) Proc Natl Acad Sci USA, 83, pp. 2797-2801
  • Davio, C., Cricco, G., Bergoc, R., Rivera, E., H1 and H2 histamine receptors in N-nitroso-N-methylurea (NMU)-induced carcinomas with atypical coupling to signal transducers (1995) Biochem Pharmacol, 50, pp. 91-96
  • Davio, C., Baldi, A., Shayo, C., Brodsky, A., Cricco, G., Bergoc, R., Rivera, E., H1 and H2 histamine receptors in histiocytic lymphoma cell line U937 (1995) Inflamm Res, 44, pp. S72-S73
  • Debburman, S.K., Kunapuli, P., Benovic, J.L., Hosey, M.M., Agonist-dependent phosphorylation of human muscarinic receptors in Spodoptera frugiperda insect cell membranes by G protein-coupled receptor kinases (1995) Mol Pharmacol, 47, pp. 224-233
  • Diviani, D., Lattion, A.L., Larbi, N., Kunapuli, P., Pronin, A., Benovic, J.L., Cotecchia, S., Effect of different G protein-coupled receptor kinases on phosphorylation and desensitization of the α1B-adrenergic receptor (1996) J Biol Chem, 271, pp. 5049-5058
  • Dohlman, H.G., Thorner, J., Caron, M.G., Lefkowitz, R., Model systems for the study of seven-transmembrane segment receptors (1991) Annu Rev Biochem, 60, pp. 653-688
  • Freedman, N., Lefkowitz, R., Desensitization of G proteins coupled-receptors (1996) Recent Prog Horm Res, 51, pp. 319-353
  • Freedman, N.J., Liggett, S.B., Brachman, D.E., Pei, G., Caron, M.G., Lefkowitz, R.J., Phosphorylation and desensitization of the human adrenergic receptor (1995) J Biol Chem, 270, pp. 17953-17961
  • Fukusima, Y., Oka, Y., Katagiri, H., Saitoh, T., Asano, T., Ishihara, H., Matsuhashi, N., Sugano, K., Desensitization of canine H2 receptor expressed in Chinese hamster ovary cells (1993) Biochem Biophys Res Commun, 190, pp. 1149-1145
  • Gantz, I., Schaffer, M., Del Valle, J., Logdson, C., Campbell, V., Uhler, M., Yamada, T., Molecular cloning a gene encoding the histamine H2 receptor (1991) Proc Natl Acad Sci USA, 88, pp. 429-433
  • Grady, E.F., Böhm, K.S., Bunnett, N.W., Turning of the signal: Mechanisms that attenuate signaling by G protein-coupled receptors (1997) Am J Physiol, 273, pp. G586-G601
  • Haga, K., Kameyama, K., Haga, T., Kikkawa, U., Shiozaki, K., Uchiyama, H., Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C (1996) J Biol Chem, 271, pp. 2776-2782
  • Hasbi, A., Polastron, J., Allouche, S., Stanasila, L., Massotte, D., Jauzac, P., Desensitization of the δ opioid receptor correlates with its phosphorylation in SK-N-BE cells: Involvement of a G protein-coupled receptor kinase (1998) J Neurochem, 70, pp. 2129-2138
  • Ishii, K., Ghen, J., Ishii, M., Koch, W.J., Freedman, N.J., Lefkowitz, R.J., Canghlin, S.R., Inhibition of thrombin receptor signaling by a G-protein coupled receptor kinase (1994) J Biol Chem, 269, pp. 1125-1130
  • Jewell-Motz, E.A., Liggett, S.B., G protein-coupled receptor kinase specificity for phosphorylation and desensitization of α2 adrenergic subtypes (1996) J Biol Chem, 271, pp. 18082-18087
  • Koch, W.J., Inglese, J., Stone, W.C., Lefkowitz, R.J., The binding site for the beta gamma subunits of heterotrimeric G proteins on the beta-adrenergic receptor kinase (1993) J Biol Chem, 268, pp. 8256-8260
  • Kwatra, M.M., Schwinn, D.A., Schreurs, J., Blank, J.L., Kim, C.M., Benovic, J.L., Krause, J.E., Lefkowitz, R.J., The substance P receptor, which couples to Gq/11, is a substrate of beta-adrenergic receptor kinase 1 and 2 (1993) J Biol Chem, 268, pp. 9161-9164
  • Kunapuli, P., Gurevich, V.V., Benovic, J.L., Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5 (1994) J Biol Chem, 269, pp. 10209-10212
  • Kurose, H., Lefkowitz, R.J., Differential desensitization and phosphorylation of three cloned and transfected α2-adrenergic receptor subtypes (1994) J Biol Chem, 269, pp. 10093-10099
  • Lemos Legnazzi, B., Shayo, C., Monczor, F., Martin, M.E., Fernandez, N., Brodsky, A., Baldi, A., Davio, C., Rapid desensitization and slow recovery of the cyclic AMP response mediated by histamine H2 receptors in U937 cell line (2000) Biochem Pharmacol, 60, pp. 159-166
  • Leurs, R., Smit, M.J., Timmerman, H., Molecular pharmacological aspects of histamine receptors (1995) Pharmacol Ther, 66, pp. 413-463
  • Lohse, M.J., Benovic, J.L., Caron, M.G., Lefkowitz, R.J., Multiple pathways of rapid β2-adrenergic receptor desensitization (1990) J Biol Chem, 265, pp. 3202-3209
  • Loudon, R.J., Benovic, J.L., Expression, purification, and characterization of the G protein-coupled receptor kinase GRK6 (1994) J Biol Chem, 269, pp. 22691-22697
  • Nakata, H., Kinoshita, Y., Kishi, K., Fukuda, H., Kawanami, C., Matsushina, Y., Asahara, M., Chiba, T., Involvement of β-adrenergic receptor kinase-1 in homologous desensitization of histamine H2 receptors in human gastric carcinoma cell line MKN-45 (1996) Digestion, 57, pp. 406-410
  • Nonaka, T., Mio, M., Doi, M., Tasaka, K., Histamine-induced differentiation of HL-60 cells. The role of cAMP and protein kinase A (1992) Biochem Pharmacol, 44, pp. 1115-1121
  • Onorato, J.J., Palczewski, K., Regan, J.W., Caron, M.G., Lefkowitz, R.J., Benovic, J.L., Role of acidic amino acids in peptide substrates of the beta-adrenergic receptor kinase and rhodopsin kinase (1991) Biochemistry, 30, pp. 5118-5125
  • Pitcher, J.A., Freedman, N.J., Lefkowitz, J., G protein-coupled receptor kinases (1998) Annu Rev Biochem, 67, pp. 653-692
  • Pitcher, J.A., Touhara, K., Payne, E.S., Lefkowitz, R.J., Pleckstrin homology domain-mediated membrane association and activation of the beta-adrenergic receptor kinase requires coordinate interaction with G beta gamma subunits and lipid (1995) J Biol Chem, 270, pp. 11707-11710
  • Premont, R.T., Koch, W.J., Inglese, J., Lefkowitz, R.J., Identification, purification, and characterization of GRK5, a member of the family of G protein-coupled receptor kinases (1994) J Biol Chem, 269, pp. 6832-6841
  • Prossnitz, E.R., Kim, C.M., Benovic, J.L., Ye, R.D., Phosphorylation of the N-formyl peptide receptor carboxyl terminus by the G protein-coupled receptor kinase, GRK2 (1995) J Biol Chem, 270, pp. 1130-1137
  • Ray, K., Kunsch, C., Bonner, L.M., Robishaw, J.D., Isolation of cDNA clones encoding eight different human G protein gamma subunits, including three novel forms designated the gamma 4, gamma 10, and gamma 11 subunits (1995) J Biol Chem, 270, pp. 21765-21771
  • Sawutz, D., Kalinyak, K., Whitsett, J., Johnson, C., Histamine H2 receptor desensitization in HL-60 human promyelocytic leukemia cells (1984) J Pharmacol Exp Ther, 231, pp. 1-6
  • Shayo, C., Davio, C., Brodsky, A., Mladovan, A., Lemos Legnazzi, B., Rivera, E., Baldi, A., Histamine modulates the expression of c-fos through cyclic AMP production via the H2 receptor in the human promonocytic cell line U-937 (1997) Mol Pharmacol, 51, pp. 983-990
  • Shetzline, M.A., Premont, R.T., Walker, J.K.L., Vigna, S.R., Caron, M.G., A role for receptor kinases in the regulation of class II G protein-coupled receptors (1998) J Biol Chem, 273, pp. 6756-6762
  • Smit, M., Leurs, R., Shukrula, S., Bast, A., Timmerman, H., Rapid desensitization of the histamine H2 receptor on the human monocytic cell line U937 (1994) Eur J Pharmacol, 288, pp. 17-25
  • Stoffel, R.H., Randall, R.R., Premont, R.T., Lefkowitz, R.J., Inglese, J., Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid modification diversity in the GRK family (1994) J Biol Chem, 269, pp. 27791-27794
  • Teramoto, H., Crespo, P., Coso, O.A., Igishi, T., Xu, N., Gutkind, J.S., The small GTP-binding protein rho activates c-Jun N-terminal kinases/stress-activated protein kinases in human kidney 293T cells. Evidence for a Pak-independent signaling pathway (1996) J Biol Chem, 271, pp. 25731-25734
  • Watson, A.J., Aragay, A.M., Slepak, V.Z., Simon, M.I., A novel form of the G protein beta subunit Gbeta5 is specifically expressed in the vertebrate retina (1996) J Biol Chem, 271, pp. 28154-28160

Citas:

---------- APA ----------
Shayo, C., Fernandez, N., Legnazzi, B.L., Monczor, F., Mladovan, A., Baldi, A. & Davio, C. (2001) . Histamine H2 receptor desensitization: Involvement of a select array of G protein-coupled receptor kinases. Molecular Pharmacology, 60(5), 1049-1056.
http://dx.doi.org/10.1124/mol.60.5.1049
---------- CHICAGO ----------
Shayo, C., Fernandez, N., Legnazzi, B.L., Monczor, F., Mladovan, A., Baldi, A., et al. "Histamine H2 receptor desensitization: Involvement of a select array of G protein-coupled receptor kinases" . Molecular Pharmacology 60, no. 5 (2001) : 1049-1056.
http://dx.doi.org/10.1124/mol.60.5.1049
---------- MLA ----------
Shayo, C., Fernandez, N., Legnazzi, B.L., Monczor, F., Mladovan, A., Baldi, A., et al. "Histamine H2 receptor desensitization: Involvement of a select array of G protein-coupled receptor kinases" . Molecular Pharmacology, vol. 60, no. 5, 2001, pp. 1049-1056.
http://dx.doi.org/10.1124/mol.60.5.1049
---------- VANCOUVER ----------
Shayo, C., Fernandez, N., Legnazzi, B.L., Monczor, F., Mladovan, A., Baldi, A., et al. Histamine H2 receptor desensitization: Involvement of a select array of G protein-coupled receptor kinases. Mol. Pharmacol. 2001;60(5):1049-1056.
http://dx.doi.org/10.1124/mol.60.5.1049