Positive allosteric modulation of α7 neuronal nicotinic acetylcholine receptors: lack of cytotoxicity in PC12 cells and rat primary cortical neurons
Article first published online: 27 NOV 2009
© 2009 Abbott Laboratories. Journal compilation © 2009 The British Pharmacological Society
British Journal of Pharmacology
Volume 158, Issue 8, pages 1857–1864, December 2009
How to Cite
Hu, M., Gopalakrishnan, M. and Li, J. (2009), Positive allosteric modulation of α7 neuronal nicotinic acetylcholine receptors: lack of cytotoxicity in PC12 cells and rat primary cortical neurons. British Journal of Pharmacology, 158: 1857–1864. doi: 10.1111/j.1476-5381.2009.00474.x
- Issue published online: 8 DEC 2009
- Article first published online: 27 NOV 2009
- Received 27 February 2009; revised 01 May 2009; accepted 28 May 2009
- α7 nAChR;
- positive allosteric modulator;
Background and purpose: α7-Nicotinic acetylcholine receptors (α7 nAChRs) play an important role in cognitive function. Positive allosteric modulators (PAMs) amplify effects of α7 nAChR agonist and could provide an approach for treatment of cognitive deficits in neuropsychiatric diseases. PAMs can either predominantly affect the apparent peak current response (type I) or increase both the apparent peak current response and duration of channel opening, due to prolonged desensitization (type II). The delay of receptor desensitization by type II PAMs raises the possibility of Ca2+-induced toxicity through prolonged activation of α7 nAChRs. The present study addresses whether type I and II PAMs exhibit different cytotoxicity profiles.
Experimental approach: The present studies evaluated cytotoxic effects of type I PAM [N-(4-chlorophenyl)]-α-[(4-chloro-phenyl)-aminomethylene]-3-methyl-5-isoxazoleacet-amide (CCMI) and type II PAM 1-[5-chloro-2,4-dimethoxy-phenyl]-3-[5-methyl-isoxazol-3-yl]-urea (PNU-120596), or 4-[5-(4chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulphonamide (A-867744). The studies used cultures of PC12 cells and primary cultures of rat cortical neuronal cells.
Key results: Our results showed that neither type I nor type II PAMs had any detrimental effect on cell integrity or cell viability. In particular, type II PAMs did not affect neuron number and neurite outgrowth under conditions when α7 nAChR activity was measured by Ca2+ influx and extracellular signal-regulated kinases 1 and 2 phosphorylation, following exposure to α7 nAChR agonists.
Conclusions and implications: This study demonstrated that both type I and type II α7 nAChR selective PAMs, although exhibiting differential electrophysiological profiles, did not exert cytotoxic effects in cells endogenously expressing α7 nAChRs.