Conferencia: Genetic, protein and pharmacological modulation of human alpha7 nicotinic receptors

BOUZAT, C.

Concepción

Congreso; XLI Congreso Anual de la Sociedad de Farmacología de Chile; 2019

The alpha7 nicotinic acetylcholine receptos is a pentamerica ligand-gated ion channel. It is widely expressed in the central nervous system where it is involved in cognition, attention and memory. It is also expressed in many non-neuronal cells and its activation has anti-inflammatory and neuroprotective roles. Enhancement of alpha7 activity is emerging as a therapeutic strategy for cognitive, neurodegenerative and inflammatory disorders. We have focused on understanding alpha7 function and its different mechanisms of modulation associated to physiological, pathological and therapeutic situations.By single-channel recordings we determined that positive allosteric modulators (PAMs) enhance alpha7 activation by increasing open-channel lifetime and inducing prolonged activation episodes, and we also identified novel PAMs. Although alpha7 has been considered the homomeric member of the family, heteromeric alpha7beta2 receptors have been detected in human brain. We generated alpha7beta2 receptors with different stoichiometries and determined how the beta2 subunit modifies alpha7 kinetics and its allosteric modulation. This information is required to decipher the role of alpha7beta2 receptors in native cells. In humans, there is a truncated alpha 7 subunit (dup7) that lacks part of the ACh-niding site and results from partial duplication of alpha7 gene. We have demonstrated that dup alpha7 acts as a negative modulator and can assemble with alpha7 into functional heteromeric receptors. Deciphering the molecular basis underlying alpha7 function has implications for the design of novel therapeutic compounds as well as for clarifying its pleiotropic actions.