<p>Insertion of nicotinic acetylcholine receptors (nAChR) into the plasma membrane depends on their movement, organization and incorporation of lipid components. nAChRs are a highly investigated target in current therapeutic research, including studies on channel opening and ion flow. Both areas require suitable cellular model systems, which are not readily available. Notably, muscle-type nAChRs can be generated in new transgene model systems. Despite minor successes, none of the existing model systems perfectly replicate the clustered, high-density receptors and their unique arrangement at the cell surface. This review examines the challenges which must be overcome to enable increased nAChR insertion into plasma membranes in artificial systems. We present models such as lipid rafts and the orchestration of protein-lipid interactions, and emphasize their relationship to nAChRs as a meshwork. Further studies reveal that membranes require particular lipid ingredients for the process of nAChR insertion. We examine the use of a picket-fence model with an extension of the dystrophin-associated glycoprotein complex (DGC) as a specialized picket for nAChR anchoring, clustering, and nanodomain formation. We specifically present the function of DGC as a special picket in nAChR platform formation for microaggregates and the signaling pathways involved in protein embedding in this DGC model. This provides insights into the issue of why nAChR insertion is minimal in artificial systems. The main aspects are evaluated by applying our transgene cellular model system. If these problems could be solved, it will be possible to develop improved cellular model systems with higher nAChR inserted densities in the future.</p> Graphical abstract <p></p>