Selected GRIN2A mutations in melanoma cause oncogenic effects that can be modulated by extracellular glutamate

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dc.contributor.author D’mello, SAN en
dc.contributor.author Joseph, Wayne en
dc.contributor.author Green, Taryn en
dc.contributor.author Leung, Yee Fun en
dc.contributor.author During, MJ en
dc.contributor.author Finlay, Graeme en
dc.contributor.author Baguley, Bruce en
dc.contributor.author Kalev, Maggie en
dc.date.accessioned 2016-12-09T01:16:45Z en
dc.date.available 2016-09-13 en
dc.date.issued 2016-12 en
dc.identifier.citation Cell Calcium, December 2016, 60 (6), 384 - 395 en
dc.identifier.issn 0143-4160 en
dc.identifier.uri http://hdl.handle.net/2292/31303 en
dc.description.abstract GRIN2A mutations are frequent in melanoma tumours but their role in disease is not well understood. GRIN2A encodes a modulatory subunit of the N-methyl-d-aspartate receptor (NMDAR). We hypothesized that certain GRIN2A mutations increase NMDAR function and support melanoma growth through oncogenic effects. This hypothesis was tested using 19 low-passage melanoma cell lines, four of which carried novel missense mutations in GRIN2A that we previously reported. We examined NMDAR expression, function of a calcium ion (Ca2+) channel and its contribution to cell growth using pharmacological modulators; findings were correlated with the presence or absence of GRIN2A mutations. We found that NMDAR expression was low in all melanoma cell lines, independent of GRIN2A mutations. In keeping with this, NMDAR-mediated Ca2+ influx and its contribution to cell proliferation were weak in most cell lines. However, certain GRIN2A mutations and culture media with lower glutamate levels enhanced NMDAR effects on cell growth and invasion. The main finding was that G762E was associated with higher glutamate-mediated Ca2+ influx and stronger NMDAR contribution to cell proliferation, compared with wild-type GRIN2A and other GRIN2A mutations. The pro-invasive phenotype of mutated cell lines was increased in culture medium containing less glutamate, implying environmental modulation of mutation effects. In conclusion, NMDAR ion channel function is low in cultured melanoma cells but supports cell proliferation and invasion. Selected GRIN2A mutations, such as G762E, are associated with oncogenic consequences that can be modulated by extracellular glutamate. Primary cultures may be better suited to determine the role of the NMDAR in melanoma in vivo. en
dc.description.uri https://www.ncbi.nlm.nih.gov/pubmed/27659111 en
dc.language English en
dc.publisher Elsevier en
dc.relation.ispartofseries Cell Calcium en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0143-4160/ https://www.elsevier.com/about/company-information/policies/sharing en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.title Selected GRIN2A mutations in melanoma cause oncogenic effects that can be modulated by extracellular glutamate en
dc.type Journal Article en
dc.identifier.doi 10.1016/j.ceca.2016.09.003 en
pubs.issue 6 en
pubs.begin-page 384 en
pubs.volume 60 en
dc.description.version VoR - Version of Record en
dc.identifier.pmid 27659111 en
pubs.author-url http://www.sciencedirect.com/science/article/pii/S0143416016301154 en
pubs.end-page 395 en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype Article en
pubs.elements-id 541850 en
pubs.org-id Medical and Health Sciences en
pubs.org-id Medical Sciences en
pubs.org-id Auckland Cancer Research en
pubs.org-id Molecular Medicine en
pubs.org-id Science en
pubs.org-id Science Research en
pubs.org-id Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1532-1991 en
pubs.record-created-at-source-date 2016-12-09 en
pubs.online-publication-date 2016-09-14 en
pubs.dimensions-id 27659111 en


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