Understanding molecular function of alpha7 nicotinic receptor towards its implementation as a clinical drug target

BOUZAT C

sAN Luis

Simposio; Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2023

Sociedad Argentina de Investigación en Neurociencias.- Human Frontiers Science Program

Insights from the molecular functional level to understand why implementing the α7 nicotinic receptor as a therapeutic drug target is so challenging.Cecilia BouzatInstituto de Investigaciones Bioquímicas de Bahía Blanca, INIBIBB (CONICET-UNS), Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Camino La Carrindanga km 7, 8000 Bahía Blanca, Argentina.The α7 nicotinic acetylcholine receptor (nAChR) is a pentameric ligand-gated ion channel expressed in the nervous system and involved in cognition, attention, and memory. It also expresses in non-neuronal cells and has anti-inflammatory and neuroprotective roles. Enhancement of α7 activity has emerged as a therapeutic strategy for neurodegenerative, neurological and inflammatory disorders. Despite promising preclinical and clinical data, no α7 specific ligand has been yet approved for clinical use. Our goal is to understand α7 molecular function and its modulation associated to physiological and pathological situations. We deciphered α7 activation at the single-channel level and revealed its great capability for modulation. We identified synthetic and natural compounds that act as novel α7 positive allosteric modulators and have neuroprotective actions; we determined that oligomeric amyloid beta peptides directly affect α7 function by acting as agonists at picomolar concentrations and as negative modulators at higher concentrations; and we demonstrated how α7 activity is modulated by phosphorylation, calcium, 2 nAChR subunits, and a truncated 7 subunit derived from a duplicated gene associated to neurological disorders. Thus, α7 function proves to be highly sensitive to different situations. By examining function from a molecular perspective, our results provide foundations for the implementation of α7 as a new therapeutic drug target.