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Affected neonates display generalized hypertonia and exaggerated startle reflex in response to innocuous stimuli, potentially leading to life-threatening apneic episodes. Although symptom severity typically diminishes during the first year of life, affected individuals often continue to exhibit disabling motor dysfunction and frequent unprotected falls throughout adulthood. Currently, no targeted therapeutic interventions are available. The pathophysiology involves partial or complete disruption of inhibitory glycinergic neurotransmission. Mutations in the gene encoding the neuronal glycine transporter GlyT2 (SLC6A5) represent the second-most frequent genetic etiology of human hyperekplexia. To investigate the mechanistic basis for the heightened severity of symptoms during the perinatal period, we examined the role of GlyT2 in neuronal differentiation using the PC12 cell model. Pharmacological induction of differentiation demonstrated that clones stably expressing GFP-GlyT2 exhibit increased expression of neuronal differentiation markers and enhanced neurite outgrowth\u2014both in number and length\u2014relative to parental PC12 cells. These clones also displayed elevated cytosolic calcium levels, which were attenuated by calmodulin overexpression, subsequently downregulating differentiation marker expression. We hereby proved that GlyT2 is clearly implicated in growth cone progression and differentiation of PC12 cells into neurons by increasing internal calcium and binding to growth cone proteins. Finally, our results were validated in primary neurons.<\/jats:p>","DOI":"10.3390\/ijms27073026","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T15:10:24Z","timestamp":1774537824000},"page":"3026","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of the Glycine Transporter GlyT2 in the Neuronal Differentiation of PC12 Cells"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8238-8885","authenticated-orcid":false,"given":"Jorge","family":"Sarmiento-Jim\u00e9nez","sequence":"first","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, Instituto de Biolog\u00eda Molecular (IUBM), Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d, Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5123-9011","authenticated-orcid":false,"given":"Beatriz","family":"Morales-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, Instituto de Biolog\u00eda Molecular (IUBM), Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d, Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"N\u00fa\u00f1ez","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, Instituto de Biolog\u00eda Molecular (IUBM), Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d, Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3683-5096","authenticated-orcid":false,"given":"Elena","family":"Mart\u00ednez-Blanco","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, Instituto de Biolog\u00eda Molecular (IUBM), Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d, Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Zafra","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, Instituto de Biolog\u00eda Molecular (IUBM), Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d, Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"IdiPAZ-Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1707-4519","authenticated-orcid":false,"given":"Francisco Javier","family":"D\u00edez-Guerra","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, Instituto de Biolog\u00eda Molecular (IUBM), Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d, Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0383-4241","authenticated-orcid":false,"given":"Beatriz","family":"L\u00f3pez-Corcuera","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, Instituto de Biolog\u00eda Molecular (IUBM), Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d, Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"IdiPAZ-Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1007\/PL00000899","article-title":"The Glycinergic Inhibitory Synapse","volume":"58","author":"Legendre","year":"2001","journal-title":"Cell. 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