Directed Mutagenesis of Nicotinic Receptors to Investigate Receptor Function

Nicotinic acetylcholine receptors (nAChR) are the archetypes of drug receptors. In 1905, John Newport Langley introduced the concept of a receptive substance on the surface of skeletal muscle that mediated the action of a drug, such as nicotine and curare (a neurotoxin made from a plant) (Langley et al., 1905). He also proposed that these receptive substances were different in different species and tissues, and they undergo conformational changes in response to the respective drug. Today nAChRs are considered prototypes of receptors that function as integral signal transducers. They have the response element and the ion channel domain within the same molecular entity as the ligand-binding domain that is activated by acetylcholine. In contrast, muscarinic acetylcholine receptors (mAChR) are prototypic G protein-coupled receptors. They also sense molecules outside the cell, but they require the G proteins to induce cellular responses by coupling to intracellular signalling pathways. More important than their historical role, nicotinic receptors continue to be at the forefront of science, as they are drug targets for muscle and nerve diseases, such as Alzheimer’s and Parkinson’s diseases, Schizophrenia and Myasthenia gravis. Therefore, this receptor family serves as an excellent example for demonstrating the suitability of site-directed mutagenesis for investigating receptor function and exploring drug action.