Identification of a Negative Allosteric Site on Human α4β2 and α3β4 Neuronal Nicotinic Acetylcholine Receptors

Acetylcholine-based neurotransmission is regulated by cationic, ligand-gated ion channels called nicotinic acetylcholine receptors (nAChRs). These receptors have been linked to numerous neurological diseases and disorders such as Alzheimer's disease, Parkinson's disease, and nicotine addiction. Recently, a class of compounds has been discovered that antagonize nAChR function in an allosteric fashion. Models of human α4β2 and α3β4 nicotinic acetylcholine receptor (nAChR) extracellular domains have been developed to computationally explore the binding of these compounds, including the dynamics and free energy changes associated with ligand binding. Through a blind docking study to multiple receptor conformations, the models were used to determine a putative binding mode for the negative allosteric modulators. This mode, in close proximity to the agonist binding site, is presented in addition to a hypothetical mode of antagonism that involves obstruction of C loop closure. Molecular dynamics simulations and MM-PBSA free energy of binding calculations were used as computational validation of the predicted binding mode, while functional assays on wild-type and mutated receptors provided experimental support. Based on the proposed binding mode, two residues on the β2 subunit were independently mutated to the corresponding residues found on the β4 subunit. The T58K mutation resulted in an eight-fold decrease in the potency of KAB-18, a compound that exhibits preferential antagonism for human α4β2 over α3β4 nAChRs, while the F118L mutation resulted in a loss of inhibitory activity for KAB-18 at concentrations up to 100 µM. These results demonstrate the selectivity of KAB-18 for human α4β2 nAChRs and validate the methods used for identifying the nAChR modulator binding site. Exploitation of this site may lead to the development of more potent and subtype-selective nAChR antagonists which may be used in the treatment of a number of neurological diseases and disorders

Risks and Challenges of Adopting Electric Vehicles in Smart Cities

Oil prices and increased carbon emissions are two of the key issues affecting mainstream transportation globally. Hence, EVs (Electric VehiclesElectric Vehicles) are becoming popular as they do not depend on oil, and the GHG (Greenhouse Gases) do not contribute to GHG emissions. In fact, their integration with smart grids makes them even more attractive. Although EVEV adoption is becoming widespread, three groups of challenges need to be addressed. These challenges are associated with EV technology adoption, integration of EVs and smart grids, and the supply chain of EV raw materials. Regarding the EV technology adoption, the risks and challenges include EV battery capacity, drivers’ range anxiety, the impact of auxiliary loads, EV drivers’ behavior, EV owners’ unwillingness to participate in the V2GV2G (Vehicle-to-Grid) program, economic barriers to adopting EVs, difficult EV maintenance, EV performance mismatch between the lab and the real world, need for government regulation, lack of charging infrastructure such as not enough charging stations, and expensive batteries. There are additional challenges concerning the integration with the smart grids such as system overload, high-cost investment in V2G technology, load mismatchLoad mismatch, and unmanaged recharging of EV batteries. Finally, there are challenges regarding the consistent supply of the raw materials needed for EVs. This chapter examines these risks and challenges, suggests solutions and provides recommendations for future research