{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T14:35:52Z","timestamp":1777905352367,"version":"3.51.4"},"reference-count":61,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2010,1,1]],"date-time":"2010-01-01T00:00:00Z","timestamp":1262304000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Mol Pain"],"published-print":{"date-parts":[[2010,1,1]]},"abstract":"<jats:sec><jats:title>Background:<\/jats:title><jats:p> The R192Q mutation of the CACNA1A gene, encoding for the \u03b11 subunit of voltage-gated P\/Q Ca<jats:sup>2+<\/jats:sup> channels (Ca<jats:sub>v<\/jats:sub>2.1), is associated with familial hemiplegic migraine-1. We investigated whether this gain-of-function mutation changed the structure and function of trigeminal neuron P2X<jats:sub>3<\/jats:sub> receptors that are thought to be important contributors to migraine pain. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p> Using in vitro trigeminal sensory neurons of a mouse genetic model knockin for the CACNA1A R192Q mutation, we performed patch clamp recording and intracellular Ca<jats:sup>2+<\/jats:sup> imaging that showed how these knockin ganglion neurons generated P2X<jats:sub>3<\/jats:sub> receptor-mediated responses significantly larger than wt neurons. These enhanced effects were reversed by the Ca<jats:sub>v<\/jats:sub> 2.1 blocker \u03c9-agatoxin. We, thus, explored intracellular signalling dependent on kinases and phosphatases to understand the molecular regulation of P2X<jats:sub>3<\/jats:sub> receptors of knockin neurons. In such cells we observed strong activation of CaMKII reversed by \u03c9-agatoxin treatment. The CaMKII inhibitor KN-93 blocked CaMKII phosphorylation and the hyperesponsive P2X<jats:sub>3<\/jats:sub> phenotype. Although no significant difference in membrane expression of knockin receptors was found, serine phosphorylation of knockin P2X<jats:sub>3<\/jats:sub> receptors was constitutively decreased and restored by KN-93. No change in threonine or tyrosine phosphorylation was detected. Finally, pharmacological inhibitors of the phosphatase calcineurin normalized the enhanced P2X<jats:sub>3<\/jats:sub> receptor responses of knockin neurons and increased their serine phosphorylation. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p> The present results suggest that the CACNA1A mutation conferred a novel molecular phenotype to P2X<jats:sub>3<\/jats:sub> receptors of trigeminal ganglion neurons via CaMKII-dependent activation of calcineurin that selectively impaired the serine phosphorylation state of such receptors, thus potentiating their effects in transducing trigeminal nociception. <\/jats:p><\/jats:sec>","DOI":"10.1186\/1744-8069-6-48","type":"journal-article","created":{"date-parts":[[2010,8,24]],"date-time":"2010-08-24T18:14:00Z","timestamp":1282673640000},"source":"Crossref","is-referenced-by-count":57,"title":["Familial Hemiplegic Migraine Ca<sub>V<\/sub>2.1 Channel Mutation R192Q Enhances ATP-gated P2X<sub>3<\/sub> Receptor Activity of Mouse Sensory Ganglion Neurons Mediating Trigeminal Pain"],"prefix":"10.1177","volume":"6","author":[{"given":"Asha","family":"Nair","sequence":"first","affiliation":[{"name":"Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy"},{"name":"Current Address: Institute for Molecules and Materials, University of Nijmegen, Toernooiveld 1, Nijmegen 6525 ED, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Simonetti","sequence":"additional","affiliation":[{"name":"Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy"},{"name":"Current Address: Pharmacology Institute, Faculty of Medicine, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicol","family":"Birsa","sequence":"additional","affiliation":[{"name":"Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel D","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Leiden University Medical Centre, Department of Neurology, 2300 RC Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arn MJM","family":"van den Maagdenberg","sequence":"additional","affiliation":[{"name":"Leiden University Medical Centre, Department of Neurology, 2300 RC Leiden, The Netherlands"},{"name":"Leiden University Medical Centre, Department of Human Genetics, 2300 RC, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rashid","family":"Giniatullin","sequence":"additional","affiliation":[{"name":"Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy"},{"name":"Department of Neurobiology, A. I. Virtanen Institute, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Nistri","sequence":"additional","affiliation":[{"name":"Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elsa","family":"Fabbretti","sequence":"additional","affiliation":[{"name":"Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy"},{"name":"University of Nova Gorica, SI-5000, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2010,1,1]]},"reference":[{"key":"bibr1-1744-8069-6-48","unstructured":"International Headache Society: The International Classification of Headache Disorders, 2nd edition. Cephalalgia 2004, 24:S1\u2013S160."},{"key":"bibr2-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e3281338d1f"},{"key":"bibr3-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81373-2"},{"key":"bibr4-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.01.027"},{"key":"bibr5-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(04)00085-6"},{"key":"bibr6-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/117.1.199"},{"key":"bibr7-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192242399"},{"key":"bibr8-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2006.11.005"},{"key":"bibr9-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0713-07.2007"},{"key":"bibr10-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0647-06.2006"},{"key":"bibr11-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800296200"},{"key":"bibr12-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-008-8020-5"},{"key":"bibr13-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2605"},{"key":"bibr14-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-007-0033-y"},{"key":"bibr15-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e32832b2427"},{"key":"bibr16-1744-8069-6-48","first-page":"731","volume":"5","author":"Durham PL","year":"2004","journal-title":"Curr Opin Investig Drugs"},{"key":"bibr17-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.t01-1-00035.x"},{"key":"bibr18-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00043.2006"},{"key":"bibr19-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.2174\/138161209788186308"},{"key":"bibr20-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.7.4.513"},{"key":"bibr21-1744-8069-6-48","first-page":"833","volume":"4","author":"North RA","year":"2003","journal-title":"Curr Opin Investig Drugs"},{"key":"bibr22-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-2-11"},{"key":"bibr23-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.023051"},{"key":"bibr24-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1124\/mi.3.7.386"},{"key":"bibr25-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2888-04.2004"},{"key":"bibr26-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-009-9483-2"},{"key":"bibr27-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4790-04.2005"},{"key":"bibr28-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)83661-4"},{"key":"bibr29-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.1.173"},{"key":"bibr30-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-4388(99)80049-X"},{"key":"bibr31-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.06.032"},{"key":"bibr32-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)84738-5"},{"key":"bibr33-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)31903-8"},{"key":"bibr34-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-199703240-00007"},{"key":"bibr35-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)99164-7"},{"key":"bibr36-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-540-33823-9_13"},{"key":"bibr37-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(94)90389-1"},{"key":"bibr38-1744-8069-6-48","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1111\/j.1399-0012.1996.tb00657.x","volume":"10","author":"Halloran PF","year":"1996","journal-title":"Clin Transplant"},{"key":"bibr39-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.8.3191"},{"key":"bibr40-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)39919-3"},{"key":"bibr41-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-07-02590.2002"},{"key":"bibr42-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20975"},{"key":"bibr43-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3809-06.2007"},{"key":"bibr44-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200409028"},{"key":"bibr45-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-07-02458.1998"},{"key":"bibr46-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1021\/bi00188a015"},{"key":"bibr47-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1038\/nrn987"},{"key":"bibr48-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.113340"},{"key":"bibr49-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1038\/nature08198"},{"key":"bibr50-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1038\/nm0202-136"},{"key":"bibr51-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4610.2005.05046.x"},{"key":"bibr52-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.023564"},{"key":"bibr53-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705701"},{"key":"bibr54-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1038\/355827a0"},{"key":"bibr55-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.1997.tb01386.x"},{"key":"bibr56-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(99)00241-9"},{"key":"bibr57-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2004.08.054"},{"key":"bibr58-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2005.06.003"},{"key":"bibr59-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.132167"},{"key":"bibr60-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2008.08.002"},{"key":"bibr61-1744-8069-6-48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-2277.2001.tb00004.x"}],"container-title":["Molecular Pain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1186\/1744-8069-6-48","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1186\/1744-8069-6-48","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1186\/1744-8069-6-48","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T03:52:38Z","timestamp":1741665158000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1186\/1744-8069-6-48"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,1,1]]},"references-count":61,"alternative-id":["10.1186\/1744-8069-6-48"],"URL":"https:\/\/doi.org\/10.1186\/1744-8069-6-48","relation":{},"ISSN":["1744-8069","1744-8069"],"issn-type":[{"value":"1744-8069","type":"print"},{"value":"1744-8069","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,1,1]]},"article-number":"1744-8069-6-48"}}