title: Age-related nuclear translocation of P2X6 subunit modifies splicing activity interacting with splicing factor 3A1.
abstract: P2X receptors are ligand-gated ion channels sensitive to extracellular nucleotides formed by the assembling of three equal or different P2X subunits. In this work we report, for the first time, the accumulation of the P2X6 subunit inside the nucleus of hippocampal neurons in an age-dependent way. This location is favored by its anchorage to endoplasmic reticulum through its N-terminal domain. The extracellular domain of P2X6 subunit is the key to reach the nucleus, where it presents a speckled distribution pattern and is retained by interaction with the nuclear envelope protein spectrin α2. The in vivo results showed that, once inside the nucleus, P2X6 subunit interacts with the splicing factor 3A1, which ultimately results in a reduction of the mRNA splicing activity. Our data provide new insights into post-transcriptional regulation of mRNA splicing, describing a novel mechanism that could explain why this process is sensitive to changes that occur with age.
authors: Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors: Juan Ignacio
authors: JI
authors: Díaz-Hernández
authors: Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors: Álvaro
authors: Á
authors: Sebastián-Serrano
authors: Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors: Rosa
authors: R
authors: Gómez-Villafuertes
authors: Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors: Miguel
authors: M
authors: Díaz-Hernández
authors: Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors: María Teresa
authors: MT
authors: Miras-Portugal
mesh_terms: D021581:Active Transport, Cell Nucleus; D000375:Aging; D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009474:Neurons / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*
chemical_list: D018048:Receptors, Purinergic P2; D017413:Ribonucleoprotein, U2 Small Nuclear; C110590:purinoceptor P2X6; C088049:splicing factor 3a