Temperature dependence of the enhancementof alpha7 nicotinic receptor activity by potential therapeutic compounds

NIELSEN, E.; ANDERSEN, N.; CORRADI, J.; BOUZAT, C.

Mar del Plata

Congreso; XXX Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2015

Sociedad Argentina de Investigación en Neurociencias (SAN)

Alpha7  nicotinic  acetylcholine  receptors  (nAChRs) are  widely  distributed throughout  the central  nervous  system,  mainly  in  hippocampus and  cortex, and  are  implicated  in  several neurological disorders such as Alzheimer´s disease and schizophrenia. Enhancement of  alpha7 nAChR activity by positive allosteric modulators (PAMs) is a promising therapeutic strategy to  improve cognitive  deficits.  PAM  activity  has  been  evaluated  mainly  at the macroscopic level,  and  PAMs  have  been  classified  as  type  I,  which increase   alpha7  currents,  and  type  II, which  cause  also  a  profound decrease in  desensitization  and/or  reactivate  desensitized receptors.  In  addition, most  in  vitro  studies  have been  performed  at  room  temperature whereas preclinical  studies  and  clinical  use  require  physiological temperatures. To  cover these  limitations  we  evaluated  potentiation  of  human   alpha7  at  the single-channel  level.  Our results  revealed  that  both  types  of  PAMs enhance  open-channel  lifetime  and  produce activation  episodes  of successive  opening   events.  By  analyzing  their  activities  at  a physiological temperature,  we  found  that  potentiation  decreases  with respect  to  room temperature.   However,   both   PAM   types   show   different sensitivity to temperature, suggesting   distinct   mechanisms   by   which   they   induce sustained   activation.   Overall, temperature dependence analysis emerges as a key requisite during evaluation of potential  clinical applications of PAMs.