In this study, we provide new gain-of-function mechanisms relevant to understand SQT3S pathogenesis, suggest the potential association of SQT3S with neurological disorders and uncover a multifunctional domain in Kir2.1 that controls pivotal properties of WT channels, such as surface expression, stability at the plasma membrane, partitioning to lipid rafts, ubiquitylation, protein degradation through proteasome and binding to Cav-2. The gene discussed is KCNJ2; the disease is nervous system disorder.