NO donors subunit and state‐dependently increase desensitization of acid sensitive ion channels

Nitric oxide donors were studied on acid‐sensing channels (ASICs) of rat striatal neurons and CHO cells expressing recombinant receptors. S‐nitroso‐acetyl‐penicillamine (SNAP) potentiate or inhibit ASICs depending on their functional state. It potentiated ASICs after pretreatment with extracellular pH 7.4. When ASICs were partially desensitized by pretreatment with pH 7.0, application of SNAP led to increase of their desensitisization. The potentiating effect of NO on ASICs is explained by an increase of ASIC proton sensitivity, whereas inhibition of ASICs by NO is due to an increase of their steady‐state desensitization. Potentiation and inhibition produced by SNAP had different subunit dependence. The most sensitive to potentiation were ASIC1a/2a and ASIC2a channels while ASIC2a and ASIC3 were the most sensitive to inhibition. Potentiation, produced by SNAP, was prevented by sulphhydryl reagent mercaptoethanol, but it did not affect inhibition produced by SNAP. Thus potentiation and inhibition seems to be mediated by different binding sites. We suppose both effects of SNAP are most probably due to nitrosylation, but not to soluble guanylate cyclase activation, because they were unaffected by ODQ, inhibitor of NO‐sensitive guanylate cyclase, and by 8‐Br‐cGMP, an activator of cGMP‐dependent PKG cascades. Work was supported by grant RFBR/STGI 09‐04‐92662‐Ind‐a.

Duke Scholars

Author Sandip Madhusudan Swain Medicine, Gastroenterology