Significance There are five KCNQ channels (KCNQ1–KCNQ5) and they are thought to either homomerize or heteromerize to form tetrameric channels. KCNQ2 and KCNQ3 are highly expressed in the brain and in particular the forebrain, the presumed site of action for many brain disorders. For the last 30 years, the prevailing view is that KCNQ potassium channels in the brain consist of KCNQ2/3 and possibly KCNQ3/5 heteromers. Here, using epitope-tagged knockin mice and split-intein–mediated protein trans-splicing experiments, we demonstrate that KCNQ2 channels form heteromers not only with KCNQ3 but also with KCNQ5 channels. Thus, our findings of unexpected KCNQ subunit composition will shift both our understanding of KCNQ genotype/phenotype relationships as well as drug screening strategies.

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