Life Sciences & Biotechnology
Title : | Alpha7 nicotinic acetylcholine receptor as a pharmacological target for treating neuronal disorders |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Kathiresan Natarajan, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | kathiresan@rgcb.res.in |
Equipments : | Dell poweredge rack server |
Details
Executive Summary : | The alpha7-nAChR (290 kDa) is a pentameric ligand-gated ion channel assembled from a ring of homologous alpha7 subunits and divided into three domains: a large ligand-binding extracellular N-terminal domain, a membrane-spanning pore, and a smaller intracellular domain with an overall length of about 160 Å normal to the membrane plane and exists in different functional states. The domain responsible for ligand binding forms an extended ⁓20 Å diameter central vestibule. It has five ACh binding sites found 40 Å from the membrane surface on opposing sides of the pore. The pore traverses the membrane in a narrow water-filled channel and holds the gate, which opens when ACh binds to the binding sites (Bondarenko et al. 2014; Chiodo et al. 2015). It leads to a spontaneous depolarization of the membrane and calcium influx. Additionally, it functions as a metabotropic receptor and recruits several signal transduction pathways. Furthermore, this receptor is also associated with neuroprotection in trauma and synaptic plasticity (Al Rawashdah et al. 2019; Shabbir et al. 2021; Zhao et al. 2021). The alpha7 nicotinic receptor is one of the most prevalent cholinergic receptors in the mammalian central nervous system (CNS). It is expressed in parts of the brain involved in learning and memory, showing a role in cognitive regulation. It is also expressed in the peripheral nervous system, immune system, and peripheral tissues. The alpha7-nicotinic receptor regulates molecular pathways involved in neurogenesis. They regulate excitatory neurotransmission, modulation of neurotransmitter release, neurite outgrowth, and potentially neuronal survival/death. Due to its pleiotropic effects, receptor malfunction or dysregulated expression is seen in several neuronal disorders. The malfunction of alpha7-nAChR has been linked to several neurological diseases such as schizophrenia, epilepsy, and stroke. Additionally, the “Cholinergic anti-inflammatory pathway” is beneficial in preventing inflammatory conditions such as sepsis and acute respiratory distress syndrome (ARDS). Neuronal agonists are useful tools for neuroscience research and may help treat a range of neurological disorders. Thus, the proposed research work will search for novel alpha7-nAChR agonists through in-silico pharmacophore-based screening and will investigate the effect of those on alpha7-nAChR. The structural insights gained from this study will help understanding the receptor kinetics and aid in structure-based drug discovery for the treatment of neuronal disorders. The outcome of this research work will pave the way for future investigations of our identified lead compounds through in-vivo studies for further characterization as potential drugs for treating neuronal disorders. |
Total Budget (INR): | 50,43,859 |
Organizations involved