Chelerythrine and other benzophenanthridine alkaloids block the human P2X7 receptor

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Abstract
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. 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. 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 μM. 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. Concentration–effect curves to ATP estimated an EC50 value of 78 μM and in the presence of 5 and 10 μM chelerythrine this increased slightly to 110 and 150 μM, respectively, which fits a noncompetitive inhibitor profile for chelerythrine. Chelerythrine at 10 μM 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%. This study demonstrates that chelerythrine in addition to PKC inhibition has a noncompetitive inhibitory action on the P2X7 receptor itself. British Journal of Pharmacology (2004) 142, 1015–1019. doi:10.1038/sj.bjp.0705868