Positive allosteric modulation of alpha‐7 nicotinic receptors promotes cell death by inducing Ca2+ release from the endoplasmic reticulum

María Guerra‐Álvarez; Ana J. Moreno‐Ortega; Elisa Navarro; José Carlos Fernández‐Morales; Javier Egea; Manuela G. López; María F. Cano‐Abad

doi:10.1111/jnc.13049

journal article Mar 06, 2015

Positive allosteric modulation of alpha‐7 nicotinic receptors promotes cell death by inducing Ca2+ release from the endoplasmic reticulum

María Guerra‐Álvarez Ana J. Moreno‐Ortega Elisa Navarro José Carlos Fernández‐Morales Javier Egea Manuela G. López

María F. Cano‐Abad

Journal of Neurochemistry Vol. 133 No. 3 pp. 309-319 · Wiley

View at Publisher Save 10.1111/jnc.13049

Abstract

AbstractPositive allosteric modulation of α7 isoform of nicotinic acetylcholine receptors (α7‐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 α7‐nAChRs (α7‐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 α7‐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 α7‐SH cells; (iv) was cytotoxic in rat organotypic hippocampal slice cultures; and, lastly, all these effects were prevented by selective blockade of α7‐nAChRs, ryanodine receptors, or IP3 receptors. In conclusion, positive allosteric modulation of α7‐nAChRs with the PAM II PNU120596 can lead to dysregulation of ER Ca2+, overloading of intracellular Ca2+, and neuronal cell death.
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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 α7‐nAChRs (α7‐SH) and their control (C‐SH), we find that PAM of α7‐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; α7 nAChR, α7 isoform of nicotinic acetylcholine receptors; α7‐SH, SH‐SY5Y stably overexpressing α7 nAChRs cells; C‐SH, control SH‐SY5Y cells; Nic, nicotine; PNU12, PNU120596.

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References

58

[1]

10.1016/0006-8993(94)91678-0

[2]

10.1097/00002093-200108001-00004

[3]

10.1016/s0028-3908(03)00317-4

[4]

10.1124/jpet.105.090365

[5]

10.1111/j.1471-4159.2009.06447.x

[6]

10.1111/j.1476-5381.2010.01034.x

[7]

10.1124/mol.105.018184

[8]

10.1016/s0306-4522(01)00280-9

[9]

10.1016/j.neuroscience.2010.10.071

[10]

10.1021/jm049363q

[11]

10.1016/j.tips.2004.04.006

[12]

10.1046/j.1471-4159.2002.00846.x

[13]

10.1002/ijc.23894

[14]

10.1093/toxsci/kfr163

[15]

10.1111/j.1471-4159.2006.04273.x

[16]

10.1111/j.1471-4159.2007.04665.x

[17]

10.1016/j.neuroscience.2006.12.036

[18]

10.1016/j.tips.2007.12.006

[19]

10.1016/j.ceca.2003.08.006

[20]

10.1016/j.ceca.2008.10.003

[21]

10.1124/mol.107.035410

[22]

10.1016/s1044-7431(03)00244-6

[23]

Muscarinic activation of ionic currents measured by a new whole-cell recording method.

R Horn, A Marty

Journal of General Physiology 10.1085/jgp.92.2.145

[24]

10.1111/j.1476-5381.2009.00474.x

[25]

10.1523/jneurosci.5269-04.2005

[26]

10.2170/jjphysiol.50.585

[27]

10.1002/ana.410420205

[28]

10.1111/j.1474-9726.2012.00858.x

[29]

10.1016/j.cbi.2010.03.007

[30]

10.1002/neu.10151

[31]

10.1016/s0006-8993(99)01372-4

[32]

10.1046/j.0953-816x.2001.01560.x

[33]

10.1074/jbc.273.45.29394

[34]

10.1016/j.ceca.2011.06.002

[35]

Fluorescent indicators for Ca2+based on green fluorescent proteins and calmodulin

Atsushi Miyawaki, Juan Llopis, Roger Heim et al.

Nature 1997 10.1038/42264

[36]

Miyawaki A. "Dynamic and quantitative Ca2+ measurements using improved cameleons" Proc Natl Acad Sci U S A. (1999) 10.1073/pnas.96.5.2135

[37]

10.1073/pnas.0400417101

[38]

10.1073/pnas.0701321104

[39]

10.1111/jnc.12641

[40]

10.1046/j.1471-4159.2003.01778.x

[41]

10.1046/j.1471-4159.2000.0742154.x

[42]

10.1016/j.freeradbiomed.2010.09.017

[43]

10.1089/ars.2012.4671

[44]

10.1021/mp300251j

[45]

10.1016/0014-5793(94)01108-7

[46]

10.2174/138945012800398874

[47]

10.1016/s0896-6273(03)00322-2

[48]

10.1016/s0006-3223(00)01100-8

[49]

10.1016/s0006-8993(97)00194-7

[50]

Soriano F. X. "Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability" J. Neurosci. (2006) 10.1523/jneurosci.0455-06.2006

Showing 50 of 58 references

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Details

Published: Mar 06, 2015
Vol/Issue: 133(3)
Pages: 309-319
License: View

Authors

M

María Guerra‐Álvarez

Servicio de Farmacología Clínica Instituto de Investigación Sanitaria Hospital Universitario de la Princesa Madrid Spain

A

Ana J. Moreno‐Ortega

Servicio de Farmacología Clínica Instituto de Investigación Sanitaria Hospital Universitario de la Princesa Madrid Spain; Instituto Teófilo Hernando Universidad Autónoma de Madrid Madrid Spain; Departamento de Farmacología y Terapéutica Facultad de Medicina Universidad Autónoma de Madrid Madrid Spain

E

Elisa Navarro

Instituto Teófilo Hernando Universidad Autónoma de Madrid Madrid Spain; Departamento de Farmacología y Terapéutica Facultad de Medicina Universidad Autónoma de Madrid Madrid Spain

J

José Carlos Fernández‐Morales

Instituto Teófilo Hernando Universidad Autónoma de Madrid Madrid Spain; Departamento de Farmacología y Terapéutica Facultad de Medicina Universidad Autónoma de Madrid Madrid Spain

J

Javier Egea

Servicio de Farmacología Clínica Instituto de Investigación Sanitaria Hospital Universitario de la Princesa Madrid Spain; Instituto Teófilo Hernando Universidad Autónoma de Madrid Madrid Spain; Departamento de Farmacología y Terapéutica Facultad de Medicina Universidad Autónoma de Madrid Madrid Spain

M

Manuela G. López

Servicio de Farmacología Clínica Instituto de Investigación Sanitaria Hospital Universitario de la Princesa Madrid Spain; Instituto Teófilo Hernando Universidad Autónoma de Madrid Madrid Spain; Departamento de Farmacología y Terapéutica Facultad de Medicina Universidad Autónoma de Madrid Madrid Spain

M

María F. Cano‐Abad

Servicio de Farmacología Clínica Instituto de Investigación Sanitaria Hospital Universitario de la Princesa Madrid Spain; Instituto Teófilo Hernando Universidad Autónoma de Madrid Madrid Spain; Departamento de Farmacología y Terapéutica Facultad de Medicina Universidad Autónoma de Madrid Madrid Spain

Funding

Ministry of Education Award: AP2009/0343

MICINN Award: FPI-UAM2012

Spanish Ministry of Health Award: RETICS-RD06/0026

Consolidación de grupos UAM-CAM Award: 1004040047

Cite This Article

María Guerra‐Álvarez, Ana J. Moreno‐Ortega, Elisa Navarro, et al. (2015). Positive allosteric modulation of alpha‐7 nicotinic receptors promotes cell death by inducing Ca2+ release from the endoplasmic reticulum. Journal of Neurochemistry, 133(3), 309-319. https://doi.org/10.1111/jnc.13049

Positive allosteric modulation of alpha‐7 nicotinic receptors promotes cell death by inducing Ca2+ release from the endoplasmic reticulum

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