Altered PLCβ/IP<sub>3</sub>/Ca<sup>2+</sup> Signaling Pathway Activated by GPRCs in Olfactory Neuronal Precursor Cells Derived from Patients Diagnosed with Schizophrenia
Zuly A. Sánchez-Florentino,
Bianca S. Romero-Martínez,
Edgar Flores-Soto,
Luis M. Montaño,
Bettina Sommer,
Marcela Valdés-Tovar,
Jesús Argueta,
Eduardo Calixto,
Arnoldo Aquino-Gálvez,
Manuel Castillejos-López,
Héctor Serrano,
Juan C. Gomez-Verjan,
Germán O. López-Riquelme,
Gloria A. Benítez-King,
Ruth Jaimez,
Héctor Solís-Chagoyán
Affiliations
Zuly A. Sánchez-Florentino
Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, CP, Mexico
Bianca S. Romero-Martínez
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, CP, Mexico
Edgar Flores-Soto
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, CP, Mexico
Luis M. Montaño
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, CP, Mexico
Bettina Sommer
Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Mexico City 14080, CP, Mexico
Marcela Valdés-Tovar
Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, CP, Mexico
Jesús Argueta
Laboratorio de Neurofarmacología, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, CP, Mexico
Eduardo Calixto
Departamento de Neurobiología, Dirección de Investigación en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, CP, Mexico
Arnoldo Aquino-Gálvez
Laboratorio de Biología Molecular, Departamento de Fibrosis Pulmonar, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Mexico City 14080, CP, Mexico
Manuel Castillejos-López
Unidad de Epidemiología Hospitalaria e Infectología, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Mexico City 14080, CP, Mexico
Héctor Serrano
Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, CP, Mexico
Juan C. Gomez-Verjan
Dirección de Investigación, Instituto Nacional de Geriatría, Mexico City 10200, CP, Mexico
Germán O. López-Riquelme
Laboratorio de Socioneurobiologia, Centro de Investigación en Ciencias Cognitivas, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, CP, Mexico
Gloria A. Benítez-King
Laboratorio de Neurofarmacología, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, CP, Mexico
Ruth Jaimez
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, CP, Mexico
Héctor Solís-Chagoyán
Laboratorio de Neurobiología Cognitiva, Centro de Investigación en Ciencias Cognitivas, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, CP, Mexico
Background: Schizophrenia (SZ) is a multifactorial chronic psychiatric disorder with a worldwide prevalence of 1%. Altered expression of PLCβ occurs in SZ patients, suggesting alterations in the PLCβ/IP3/Ca2+ signaling pathway. This cascade regulates critical cellular processes in all cell types, including the neuronal lineage; however, there is scarce evidence regarding the functionality of this transduction signaling in neuronal cells derived from SZ patients. Objective: We evaluated the functionality of the PLCβ/IP3/Ca2+ pathway in olfactory neuronal precursor cells (hONPCs) obtained from SZ patients. Methods: Cryopreserved hONPCs isolated from SZ patients and healthy subjects (HS) were thawed. The cellular types in subcultures were corroborated by immunodetection of the multipotency and lineage markers SOX-2, Musashi-1, nestin, and β-III tubulin. The PLCβ/IP3/Ca2+ pathway was activated by GPCR (Gq) ligands (ATP, UTP, serotonin, and epinephrine). In addition, PLCβ and IP3R were directly stimulated by perfusing cells with the activators m-3M3FBS and ADA, respectively. Cytosolic Ca2+ was measured by microfluorometry and by Ca2+ imaging. The amount and subcellular distribution of the PLCβ1 and PLCβ3 isoforms were evaluated by confocal immunofluorescence. IP3 concentration was measured by ELISA. Results: The results show that the increase of cytosolic Ca2+ triggered by GPCR ligands or directly through either PLCβ or IP3R activation was significantly lower in SZ-derived hONPCs, regarding HS-derived cells. Moreover, the relative amount of the PLCβ1 and PLCβ3 isoforms and IP3 production stimulated with m-3M3FBS were reduced in SZ-derived cells. Conclusions: Our results suggest an overall functional impairment in the PLCβ/IP3/Ca2+ signaling pathway in SZ-derived hONPCs.
