title: Chelerythrine and other benzophenanthridine alkaloids block the human P2X7 receptor.
abstract: 1 Extracellular ATP can activate a cation-selective channel/pore on human B-lymphocytes, known as the P2X7 receptor. Activation of this receptor is linked to PLD stimulation. We have used ATP-induced 86Rb+ (K+) efflux to examine the effect of benzophenanthridine alkaloids on P2X7 channel/pore function in human B-lymphocytes. 2 Both ATP and the nucleotide analogue 2'-3'-O-(4-benzoylbenzoyl)-ATP (BzATP) induced an 86Rb+ efflux, which was completely inhibited by the isoquinoline derivative 1-(N,O-bis[5-isoquinolinesulphonyl]-N-methyl-l-tyrosyl)-4-phenylpiperazine (KN-62), a potent P2X7 receptor antagonist. 3 The benzophenanthridine alkaloid chelerythrine, a potent PKC inhibitor, inhibited the ATP-induced 86Rb+ efflux by 73.4+/-3.5% and with an IC50 of 5.6+/-2.3 microm. Similarly, other members of this family of compounds, sanguinarine and berberine, blocked the ATP-induced 86Rb+ efflux by 58.8+/-4.8 and 61.1+/-8.0%, respectively. 4 Concentration-effect curves to ATP estimated an EC50 value of 78 microm and in the presence of 5 and 10 microm chelerythrine this increased slightly to 110 and 150 microm, respectively, which fits a noncompetitive inhibitor profile for chelerythrine. 5 Chelerythrine at 10 microm was effective at inhibiting the ATP-induced PLD stimulation in B-lymphocytes by 94.2+/-21.9% and the phorbol 12-myristate 13-acetate-induced PLD stimulation by 68.2+/-7.4%. 6 This study demonstrates that chelerythrine in addition to PKC inhibition has a noncompetitive inhibitory action on the P2X7 receptor itself.
authors.affiliation: Department of Medicine, The University of Sydney at Nepean Hospital, Penrith, NSW, 2751, Australia.
authors.forename: Anne N
authors.initials: AN
authors.lastname: Shemon
authors.forename: Ronald
authors.initials: R
authors.lastname: Sluyter
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Conigrave
authors.forename: James S
authors.initials: JS
authors.lastname: Wiley
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D053119:Benzophenanthridines; D001599:Berberine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines; D007700:Kinetics; D010617:Phenanthridines / Q000494:pharmacology*; D010739:Phospholipase D / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000502:physiology; D058486:Receptors, Purinergic P2X7; D012414:Rubidium Radioisotopes / Q000493:pharmacokinetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D007546:Isoquinolines; C546468:P2RX7 protein, human; D010617:Phenanthridines; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D012414:Rubidium Radioisotopes; D001599:Berberine; D000255:Adenosine Triphosphate; C005705:sanguinarine; C016299:chelerythrine; D011493:Protein Kinase C; D010739:Phospholipase D; D013755:Tetradecanoylphorbol Acetate