Project 434925

Nicotinic acetylcholine receptors (nAChRs) are signaling proteins that play a central role in the communication between nerves and muscle. At the neuromuscular junction, the nAChR converts the chemical signal received from the nerve, acetylcholine, into an electric impulse leading to muscle contraction. Altered nAChR function at the neuromuscular junction leads to a disease known as Congenital Myasthenic Syndrome or CMS. CMS is characterized by muscle weakness, respiratory difficulties, reduced mobility and delayed motor milestones. Genetic mutations leading to CMS ultimately impair how the body controls muscle contraction. To date, over 350 CMS-causing mutations have been identified, with approximately half of these located in genes encoding for the nAChR. Some CMS-causing mutations alter the expression levels, the amount of nAChRs at the muscle surface, to impair neuromuscular function. Others alter how the nAChR responds to its stimulus, acetylcholine, to impair neuromuscular communication. In this research project, we will study the structure of the nAChR and will learn how disease-causing mutations alter nAChR function in order to pinpoint "sites" that can be targeted by small molecule drugs to correct the disease-causing behavior. By understanding the pathological basis for the disease, we will devise new treatments to ameliorate or cure CMS.