Histamine receptor-dependent and/or -independent activation of guanine nucleotide-binding proteins by histamine and 2-substituted histamine derivatives in human leukemia (HL-60) and human erythroleukemia (HEL) cells

N1-(3-Cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-AK57), a Potent Partial Agonist for the Human Histamine H1- and H2-Receptors

“…H 1 R agonists of the 2-phenylistamine class are cationic-amphiphilic compounds and efficient direct G-protein activators in some systems (Seifert et al, 1994;Hagelü ken et al, 1995). To exclude direct G-protein activation as mechanism for the GTPase stimulation by UR-AK57, which is cationic-amphiphilic as well, we studied the effects of the first-generation H 1 R antagonists mepyramine, promethazine, diphenhydramine, triprolidine, and cyproheptadine, as well as the secondgeneration H 1 R antagonists terfenadine and fexofenadine, on GTP hydrolysis stimulated by UR-AK57 (1 M) (Fig.…”

“…Because AIPGs are cationic-amphiphilic and compounds with such properties can activate G-proteins directly (Seifert et al, 1994;Hagelü ken et al, 1995), it was important to exclude the possibility of direct G-protein activation by AIPGs. Direct G-protein-stimulatory effects of histamine receptor ligands are usually observed at concentrations of Ͼ10 to 100 M (Seifert et al, 1994;Hagelü ken et al, 1995), but the stimulatory effects of UR-AK57 on GTP hydrolysis in membranes expressing hH 1 R were already apparent at a concentration as low as 100 nM (Fig.…”

“…The molecular basis for the differences in pharmacological properties between hH 1 R and gpH 1 R has recently been elucidated (Bruysters et al, 2005). A further complication is that, at concentrations in the range of 10 M to 1 mM, 2-phenylhistamines may activate G-proteins directly, i.e., in a receptor-independent manner (Seifert et al, 1994;Hagelü ken et al, 1995;Klinker et al, 1996).…”

How do basic secretagogues activate mast cells?

“…While a certain degree of G-protein and cell type specificity of the pharmacological effects of CADs could be obtained (Higashijima et al 1990;Hagelüken et al 1995b;Sukumar et al 1997) and Gproteins were suggested to constitute pharmacological targets on their own right, the pleiotropic actions of CADs and negatively charged G-protein inhibitors were a serious concern (Freissmuth et al 1999). For these reasons, very little research has been performed in the field since then.…”

“…It is reasonable to assume that both GPCR-dependent and GPCR-independent mechanisms are involved in CAD-induced pseudo-allergy. For 2-phenylhistamines, histamine H 1 -receptor-dependent and H 1 -receptor-independent G-protein-mediated effects have already been documented (Hagelüken et al 1995b;Seifert et al 1994Seifert et al , 2013. Understanding the mechanism of CAD action is not only of academic interest but also of therapeutic relevance because direct G-protein activation is expected to be less accessible to pharmacological intervention than GPCRmediated mechanisms.…”