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ASIC1a and ASIC2a, two of the most highly expressed subunits in the brain, form functional homo- and hetero-meric (ASIC1a\/2a) channels. The function of ASIC1a has been widely studied using psalmotoxin (PcTx1), a venom-derived peptide, as an ASIC1a-selective antagonist. Here, using whole-cell patch clamp, we show that PcTx1 has dual actions at ASIC1a\/2a. It can either inhibit or potentiate the heteromeric channel, depending on the conditioning and stimulating pHs. Potent inhibition occurs only at conditioning pHs that begin to desensitize the channel (IC<jats:sub>50<\/jats:sub>\u2009=\u20092.9\u2009nM at pH7.0, a threshold pH for desensitization of ASIC1a\/2a). By contrast, potent potentiation can occur at the physiological pH in both CHO cells (EC<jats:sub>50<\/jats:sub>\u2009=\u200956.1\u2009nM) and cortical neurons (threshold concentration\u2009&lt;\u200910\u2009nM). PcTx1 potentiates ASIC1a\/2a by increasing the apparent affinity of channel activation for protons. As such, potentiation is the strongest at moderate pHs, diminishing with increasing proton concentrations. Our findings identify PcTx1 as a valuable tool for studying ASIC1a\/2a function and contribute significantly to the understanding of the diverse and complex pharmacology of PcTx1.<\/jats:p>","DOI":"10.1038\/s41598-018-25386-9","type":"journal-article","created":{"date-parts":[[2018,5,1]],"date-time":"2018-05-01T14:54:05Z","timestamp":1525186445000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a\/2a)"],"prefix":"10.1038","volume":"8","author":[{"given":"Yi","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Hagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Schoellerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,5,8]]},"reference":[{"key":"25386_CR1","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/386173a0","volume":"386","author":"R Waldmann","year":"1997","unstructured":"Waldmann, R., Champigny, G., Bassilana, F., Heurteaux, C. & Lazdunski, M. 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