Ligand Induced Changes in the Assembly of Nicotinic Receptors

Abstract

Tobacco smoking is the leading cause of preventable death in the world. Nicotine the primary compound found in tobacco smoke has been found to alter the assembly of some subtypes of nicotinic receptors. Although the mechanism of nicotine addiction is not clearly understood, it is hypothesized that nicotine interacts with the nicotinic receptors during assembly in ER and alters trafficking to plasma membrane. Nicotinic receptors located in the brain are pentameric ion channel composed of alpha (α2-10) and beta (β2-4) subunits. The α4β2 is the primary nicotinic receptors subtype found in the brain and can have low and high sensitive stoichiometries which differ in ion channel sensitivity, conductivity, and desensitization ability. We developed a single molecule based technique which enables us to isolate single receptors in nanoscale membrane derived vesicles and employed this method to study the stoichiometry of nicotinic receptors. We show that like the nicotine, other nicotinic receptor ligands also alter the stoichiometry and trafficking of α4β2.