Simposio

BOUZAT C

Granada

Congreso; 11th IBRO World Congress; 2023

International Brain Research Organization - IBRO

Understanding molecular function of 7 nicotinic receptor towards its implementation as a clinical drug target 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 widely expressed in the central nervous system where it is involved in cognition, attention, and memory. It is also expressed in non-neuronal cells and has anti-inflammatory and neuroprotective roles. Enhancement of α7 nAChR activity is emerging as a therapeutic strategy for neurodegenerative, cognitive and inflammatory disorders; many α7 nAChR ligands have been developed and some of them have been tested in clinical trials. However, despite promising preclinical data and clinical data, no α7 nAChR specific ligand has been yet approved for clinical use. Our goal is to understand α7 nAChR function and its modulation associated to physiological and pathological situations to contribute to its implementation as a therapeutic target. To this end, we deciphered α7 nAChR activation at the single-channel level and revealed its great capability for modulation. We identified synthetic and natural compounds that behave as novel α7 nAChR positive allosteric modulators and have neuroprotective actions; we determined that oligomeric amyloid beta peptides directly affect α7 nAChR function by acting as agonists at picomolar concentrations and as negative modulators at concentrations found in Alzheimer’s disease patients; and we demonstrated how α7 nAChR activity is modulated by the Spike protein of the SARS-CoV-2 virus, by calcium, by 2 nAChR subunits, and by a truncated 7 subunit derived from a duplicated gene associated to neurological disorders. Thus, α7 nAChR function proves to be highly sensitive to different situations. Overall, by examining function from a molecular perspective, our results provide foundations for understanding cholinergic signaling mediated by α7 nAChR and its potential as a new therapeutic drug targe