Molecular function of alpha7 nicotinic receptors

BOUZAT, C.

Castellon

Conferencia; 6th International Iberian Biophysics Congress-X Iberoamerican Congress of Biophysics; 2018

6th International Iberian Biophysics Congress X Iberoamerican Congress of Biophysics

The α 7 nicotinic receptor is expressed in brain and non-neuronal cells. Enhancement of α 7 activity by positive allosteric modulators (PAMs) is emerging as a therapeutic strategy for cognitive and inflammatory disorders. We have focused on understanding α 7 function and potentiation. We revealed that PAMs enhance α 7 activation by increasing the open-channel lifetime andinducing prolonged activation episodes. Although α 7 has been considered the homomeric member of the family, a novel α 7ß2 receptor has been recently discovered in human brain. We generated α 7ß2 receptors with fixed stoichiometry by two approaches comprising concatenatedand unlinked subunits. We found that ß2 can assemble with α 7 subunits resulting in receptorswith different stoichiometries, kinetic signatures and PAM selectivity. This information provides fundamental basis required to decipher the role of α 7ß2 in native cells. In humans, thereis a truncated α 7 subunit (dupα 7) that lacks part of the ACh-binding site and results from a partial duplication of the α 7 gene. Its role remains unknown. We demonstrated that dupα 7 actsas a negative modulator, cannot form channels, but can assemble with α 7 into functional heteromeric receptors. Deciphering the molecular basis underlying a7 responses has implicationsfor the design of novel therapeutic compounds.