PENTAMERIC LIGAND-GATED ION CHANNELS: FROM MOLECULE TO MEDICINE

BOUZAT, C .

Mar del Plata

Conferencia; REUNIÓN CONJUNTA SAIC SAB AAFE AACYTAl 2023; 2023

PENTAMERIC LIGAND-GATED ION CHANNELS: FROM MOLECULE TO MEDICINECECILIA BOUZATInstituto de Investigaciones Bioquímicas de Bahía Blanca- CONICET- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Universidad Nacional del Sur.Pentameric ligand-gated ion channels (pLGICs) mediate ionotropic responses in vertebrates and invertebrates. These receptors are vital for converting neurotransmitter recognition into electrical impulses, contributing to essential physiological processes such as movement, memory, cognition, and plasticity. They are found in the central and peripheral nervous systems, as well as in various non-neuronal cells, and are associated with a wide range of disorders, making them significant pharmacological targets for clinically relevant drugs. In vertebrates, the pLGIC family includes the cation-selective channels, nicotinic acetylcholine receptors (nAChRs) and 5-hydroxytryptamine type 3 receptors, and the anion-selective channels, glycine and gamma-aminobutyric acid type A receptors. In invertebrates, the repertoire of pLGICs is even more diverse, encompassing anionic channels activated by glutamate, acetylcholine, and biogenic amines. Remarkably, the free-living nematode Caenorhabditis elegans, which serves as a model for human diseases and anthelmintic drug discovery, possesses one of the largest and most diverse receptor families. As a result, C. elegans is an ideal organism for investigating the biology and pharmacology of pLGICs and exploring their potential as targets for novel therapeutic interventions. Through the use of heterologous expression systems and patch clamp recordings of wild-type and mutant pLGICs, particularly α7 nAChRs and 5-HT3A receptors, we have elucidated the molecular mechanisms of their operation. Our studies have deciphered the kinetics and pharmacological peculiarities that enable these receptors to adapt to their physiological roles and have identified new compounds with therapeutic potential for neurological and neurodegenerative disorders. In C. elegans, our studies ranging from the molecular to the organism level have provided insights into novel aspects of pLGIC pharmacology and function as well as their physiological roles. Furthermore, these studies have identified novel receptor targets and attractive lead compounds for anthelmintic drug therapy. Overall, our studies lay the foundation for the design and development of therapies that can effectively target and modulate pLGICs for improved clinical outcomes.