From the H2 receptor gene to reclassification of the H2 receptor antagonists

From previous studies it is known that long-term stimulation of the histamine H₂ receptor results in receptor downregulation. Two different pathways are involved in the downregulation process of the H₂ receptor: a cAMP-dependent and cAMP-independent agonist-dependent pathway. Recently, it became evident that in the absence of an agonist the H₂ receptor expressed in CHO cells already stimulate cAMP production, also referred to as spontaneous activity. The spontaneous activity can be inhibited by several H₂ 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.