MinK-related peptides (MiRPs) are single transmembrane proteins that associate with mammalian voltagegated K ؉ subunits. Here we report the cloning and functional characterization of a MiRP ␤-subunit, MPS-1, and of a voltage-gated pore-forming potassium subunit, KVS-1, from the nematode Caenorhabditis elegans. mps-1 is expressed in chemosensory and mechanosensory neurons and co-localizes with kvs-1 in a subset of these. Inactivation of either mps-1 or kvs-1 by RNA interference (RNAi) causes partially overlapping neuronal defects and results in broad-spectrum neuronal dysfunction, including defective chemotaxis, disrupted mechanotransduction, and impaired locomotion. Inactivation of one subunit by RNAi dramatically suppresses the expression of the partner subunit only in cells where the two proteins co-localize. Co-expression of MPS-1 and KVS-1 in mammalian cells gives rise to a potassium current distinct from the KVS-1 current. Taken together these data indicate that potassium currents constitute a basic determinant for C. elegans neuronal function and unravel a unifying principle of evolutionary significance: that potassium channels in various organisms use MiRPs to generate uniqueness of function with rich variation in the details.MinK-related peptides (MiRPs or KCNEs) 1 are single-transmembrane proteins that associate with pore-forming ion-channel subunits to form stable complexes with channel properties markedly distinct from those of the isolated pore-forming subunits (1, 2). MiRPs were identified recently in an attempt to find a ␤-subunit for the cardiac potassium channel HERG, which in heterologous expression systems behaves differently than in native cardiomyocytes. Using in silico approaches three MiRPs (MiRP1, MiRP2, and MiRP3) were recognized by their homology with MinK, a putative ␤-subunit of HERG and KCNQ1 (2-5). The last member of the family, MiRP4 was identified later (6). Although MiRPs were initially identified as cardiac proteins, they were soon found to be expressed and function in other tissues and to cause acquired and congenital disease (2, 7-11). For instance, MiRP2 is expressed in skeletal muscle where it associates with Kv3.4 and, when defective, can cause periodic paralysis (8). Mutations in MinK and MiRP1 genes can lead to Long QT syndrome, a specific form of polymorphic ventricular tachycardia characterized by impaired ventricular repolarization (2, 10 -12). A well-established characteristic of MiRPs is the capacity to associate with multiple pore-forming subunits in heterologous systems. For instance, MiRP1 can associate with HERG, KCNQ1, HCN, and Kv4.2 subunits (2, 13-15). Indeed, MiRP "promiscuity" has considerable biomedical implications, because, if a single MiRP coassembles with multiple pore-forming subunits, genetic mutations would be predicted to lead to disruption of multiple currents simultaneously.To date MiRPs have been reported only in vertebrates, suggesting that MiRPs might be relatively young in the evolutionary scale. We speculated that they might underlie a more ge...