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Pacemaker dorsal unpaired median neurons isolated from the cockroach central nervous system were used to study the effects of toxin\u2003VII. In current\u2010clamp, 50\u2003n<jats:sc>m<\/jats:sc> toxin\u2003VII produced a membrane depolarization and reduced spiking. At 200\u2003n<jats:sc>m<\/jats:sc>, depolarization associated with multiphasic effects was seen. After artificial hyperpolarization, plateau potentials on which spontaneous electrical activity appeared were observed. In voltage clamp, toxin\u2003VII induced a negative shift of the voltage dependence of sodium current activation without significant effect on steady\u2010state inactivation. In addition, toxin\u2003VII produced a permanent TTX\u2010sensitive holding inward current, indicating that background sodium channels were targeted by \u03b2\u2010toxin. Cell\u2010attached patch recordings indicated that these channels were switched from unclustered single openings to current fluctuating between distinct subconductance levels exhibiting increased open probability and open\u2010time distribution. Toxin\u2003VII also produced a TTX\u2010sensitive [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> rise. Immunostaining with Cav2.2(\u03b11b) antibodies and calcium imaging data obtained with \u03c9\u2010CgTx GVIA indicated that N\u2010type high\u2010voltage\u2010activated calcium channels initiated calcium influx and were an essential intermediate in the pathway linking toxin\u2003VII\u2010modified sodium channels to the activation of an additional route for calcium entry. By using inhibitors of (i) noncapacitative calcium entry (inhibitor LOE\u2010908), (ii) NO\u2010sensitive guanylyl cyclase (ODQ) and (iii) phosphodiesterase\u20032 (EHNA), together with cGMP antibodies, we demonstrated that noncapacitative calcium entry was the final step in a complex combination of events that was initiated by toxin\u2003VII\u2010alteration of sodium channels and then involved successive activation of other membrane ion channels.<\/jats:p>","DOI":"10.1111\/j.1460-9568.2006.04667.x","type":"journal-article","created":{"date-parts":[[2006,3,21]],"date-time":"2006-03-21T14:15:09Z","timestamp":1142950509000},"page":"1465-1478","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Indirect activation of neuronal noncapacitative Ca<sup>2+<\/sup> entry is the final step involved in the neurotoxic effect of <i>Tityus serrulatus<\/i> scorpion \u03b2\u2010toxin"],"prefix":"10.1111","volume":"23","author":[{"given":"Fran\u00e7oise","family":"Grolleau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Stankiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Kielbasiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010France","family":"Martin\u2010Eauclaire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Lavialle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"De Vente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Lapied","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,3,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1998.80.5.2718"},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","first-page":"12553","DOI":"10.1016\/S0021-9258(18)33546-4","article-title":"Tityus serrulatus venom contains two classes of toxins. 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