title: From the H(2) receptor gene to reclassification of the H(2) receptor antagonists.
abstract: From previous studies it is known that long-term stimulation of the histamine H(2) receptor results in receptor downregulation. Two different pathways are involved in the downregulation process of the H(2) receptor: a cAMP-dependent and cAMP-independent agonist-dependent pathway. Recently, it became evident that in the absence of an agonist the H(2) receptor expressed in CHO cells already stimulate cAMP production, also referred to as spontaneous activity. The spontaneous activity can be inhibited by several H(2) antagonists, previously thought to act as competitive antagonists, and these antagonists are referred to as inverse agonists. Some antagonists, e.g. burimamide, are not able to inhibit the spontaneous activity and are referred to as neutral antagonists. Inverse agonism appears to be the mechanistic basis of upregulation. Only inverse agonists and not neutral antagonists induce receptor upregulation after long-term treatment as these compounds inhibit the spontaneous receptor activity and thus the basal receptor downregulation. Moreover it might also explain previously reported observations after long-term treatment of gastric ulcers, such as intragastric hyperacidity.
authors: Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
authors: A E
authors: AE
authors: Alewijnse
references: Mol Pharmacol. 1994 Mar;45(3):524-31
references: 8145737
references: J Biol Chem. 1994 Apr 22;269(16):11687-90
references: 7909313
references: Synapse. 1993 Nov;15(3):209-20
references: 7904088
references: Biochem Biophys Res Commun. 1994 Feb 15;198(3):1195-202
references: 8117277
references: Gut. 1991 Dec;32(12):1455-60
references: 1685465
references: J Mol Med (Berl). 1995 Feb;73(2):51-63
references: 7627630
references: J Biol Chem. 1994 Oct 21;269(42):25970-3
references: 7929307
references: J Biol Chem. 1993 Aug 5;268(22):16483-7
references: 8393865
references: Biochem Biophys Res Commun. 1993 Feb 15;190(3):1149-55
references: 8382488
references: Mol Pharmacol. 1994 Mar;45(3):390-4
references: 7908404
references: Agents Actions. 1989 Nov;28(3-4):215-7
references: 2531973
references: Biochem Biophys Res Commun. 1991 Sep 30;179(3):1470-8
references: 1930188
references: Proc Natl Acad Sci U S A. 1990 Apr;87(8):2896-900
references: 2158097
references: Agents Actions Suppl. 1991;33:257-69
references: 1828932
references: J Biol Chem. 1993 Oct 25;268(30):22273-6
references: 8226735
references: Biochem Biophys Res Commun. 1995 Jun 15;211(2):570-7
references: 7794271
references: Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6802-7
references: 8692899
references: Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):429-33
references: 1703298
references: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2649-53
references: 1313563
references: Gastroenterology. 1994 Jan;106(1):60-4
references: 8276209
references: Mol Pharmacol. 1996 Dec;50(6):1479-86
references: 8967968
references: Mol Pharmacol. 1991 Feb;39(2):192-8
references: 1847493
references: Biochem Biophys Res Commun. 1991 Aug 15;178(3):1386-92
references: 1714721
references: Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):2979-83
references: 1849641
references: Biochem J. 1997 Aug 1;325 ( Pt 3):733-9
references: 9271095
references: Biochem J. 1994 Nov 1;303 ( Pt 3):803-8
references: 7980449
references: Pharmacol Ther. 1995 Jun;66(3):413-63
references: 7494855
references: Biochim Biophys Acta. 1993 Nov 7;1179(2):171-88
references: 7692969
references: Am J Physiol. 1993 Nov;265(5 Pt 1):G987-92
references: 7694503
references: Eur J Pharmacol. 1994 Dec 15;288(1):17-25
references: 7705464
references: Mol Pharmacol. 1994 Mar;45(3):490-9
references: 7908406
references: J Biol Chem. 1992 Jan 25;267(3):1430-3
references: 1346134
references: J Biol Chem. 1996 Mar 29;271(13):7574-82
references: 8631790
references: J Biol Chem. 1992 Feb 15;267(5):3530-8
references: 1371121
references: Mol Pharmacol. 1989 Aug;36(2):248-55
references: 2549382
references: Biochem J. 1995 May 15;308 ( Pt 1):275-81
references: 7538756
references: J Biol Chem. 1994 Nov 11;269(45):27925-31
references: 7525564
references: J Biol Chem. 1993 Mar 5;268(7):4625-36
references: 8095262