Guerra-Alvarez 2015 J Neurochem

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Guerra-Álvarez M, Moreno-Ortega AJ, Navarro E, FernÑndez-Morales JC, Egea J, López MG, Cano-Abad MF (2015) Positive allosteric modulation of alpha-7 nicotinic receptors promotes cell death by inducing Ca2+ release from the endoplasmic reticulum. J Neurochem 133:309-19.

Β» PMID: 25650007

Guerra-Alvarez M, Moreno-Ortega AJ, Navarro E, Fernandez-Morales JC, Egea J, Lopez MG, Cano-Abad MF (2015) J Neurochem

Abstract: Positive allosteric modulation of Ξ±7 isoform of nicotinic acetylcholine receptors (Ξ±7-nAChRs) is emerging as a promising therapeutic approach for central nervous system disorders such as schizophrenia or Alzheimer's disease. However, its effect on Ca2+ signaling and cell viability remains controversial. This study focuses on how the type II positive allosteric modulator (PAM II) PNU120596 affects intracellular Ca2+ signaling and cell viability. We used human SH-SY5Y neuroblastoma cells overexpressing Ξ±7-nAChRs (Ξ±7-SH) and their control (C-SH). We monitored cytoplasmic and endoplasmic reticulum (ER) Ca2+ with Fura-2 and the genetically encoded cameleon targeting the ER, respectively. Nicotinic inward currents were measured using patch-clamp techniques. Viability was assessed using methylthiazolyl blue tetrazolium bromide or propidium iodide staining. We observed that in the presence of a nicotinic agonist, PNU120596 (i) reduced viability of Ξ±7-SH but not of C-SH cells; (ii) significantly increased inward nicotinic currents and cytosolic Ca2+ concentration; (iii) released Ca2+ from the ER by a Ca2+ -induced Ca2+ release mechanism only in Ξ±7-SH cells; (iv) was cytotoxic in rat organotypic hippocampal slice cultures; and, lastly, all these effects were prevented by selective blockade of Ξ±7-nAChRs, ryanodine receptors, or IP3 receptors. In conclusion, positive allosteric modulation of Ξ±7-nAChRs with the PAM II PNU120596 can lead to dysregulation of ER Ca2+ , overloading of intracellular Ca2+ , and neuronal cell death. This study focuses on how the type II positive allosteric modulator PNU120596 (PAM II PNU12) affects intracellular Ca2+ signaling and cell viability. Using SH-SY5Y neuroblastoma cells overexpressing Ξ±7-nAChRs (Ξ±7-SH) and their control (C-SH), we find that PAM of Ξ±7-nAChRs with PNU120596: (i) increases inward calcium current (ICa ) and cytosolic Ca2+ concentration ([Ca2+ ]cyt ); (ii) releases Ca2+ from the ER ([Ca2+]ER ) by a Ca2+ -induced Ca2+ release mechanism; and (iv) reduces cell viability. These findings were corroborated in rat hippocampal organotypic cultures. [Ca2+]cyt , cytosolic Ca2+ concentration; [Ca2+]ER , endoplasmic reticulum Ca2+ concentration; Ξ±7 nAChR, Ξ±7 isoform of nicotinic acetylcholine receptors; Ξ±7-SH, SH-SY5Y stably overexpressing Ξ±7 nAChRs cells; C-SH, control SH-SY5Y cells; Nic, nicotine; PNU12, PNU120596.

Β© 2015 International Society for Neurochemistry. β€’ Keywords: Ca2+, D1-ER cameleon probe, Cytotoxicity, Positive allosteric modulators, Ξ±7 nicotinic receptors


Labels: Pathology: Alzheimer's 

Organism: Human, Rat  Tissue;cell: Nervous system 






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