Molecular function of the novel alpha7beta2 nicotinic receptor

NIELSEN, BEATRIZ E.; MINGUEZ, TERESA; BERMUDEZ, ISABEL; BOUZAT, CECILIA

CELL. MOLEC. LIFE SCIEN.

Springer

Año: 2018 vol. 75 p. 2457 - 2471

1420-682X

The α7 nicotinic receptor is a promising drug target for neurological and infammatory disorders. Although it is the homomeric member of the family, a novel α7β2 heteromeric receptor has been discovered. To decipher the functional contribution of the β2 subunit, we generated heteromeric receptors with fxed stoichiometry by two diferent approaches comprising concatenated and unlinked subunits. Receptors containing up to three β2 subunits are functional. As the number of β2 subunits increases in the pentameric arrangement, the durations of channel openings and activation episodes increase progressively probably due to decreased desensitization. The prolonged activation episodes conform the kinetic signature of α7β2 and may have an impact on neuronal excitability. For activation of α7β2 receptors, an α7/α7 binding-site interface is required, thus indicating that the three β2 subunits are located consecutively in the pentameric arrangement. α7-positive allosteric modulators (PAMs) are emerging as novel therapeutic drugs. The presence of β2 in the pentamer afects neither type II PAM potentiation nor activation by an allosteric agonist whereas it impairs type I PAM potentiation. This frst single-channel study provides fundamental basis required to decipher the role and function of the novel α7β2 receptor and opens doors to develop selective therapeutic drugs.