KCNQ2 and KCNQ5 can form a channel complex in the brain independent of KCNQ3 channels

ABSTRACT: KCNQ2 and KCNQ3 channels are associated with multiple neurodevelopmental disorders and are also therapeutic targets for neurological and neuropsychiatric diseases. The current dogma is that, in the brain, KCNQ2 forms diheteromeric channels with KCNQ3, but not with KCNQ5, a channel also resident in neurons. Here, we investigated whether KCNQ2 channels can form functional triheteromeric channels with KCNQ3 and KCNQ5. We applied split-intein-mediated protein trans-splicing to form KCNQ2-KCNQ5 diheteromeric channels followed by co-expression with KCNQ3 to form triheterometic channels. Unexpectedly, we found that KCNQ2-KCNQ5 tandems can form functional channels that are regulated by KCNQ3 and PIP2 levels. Using an epitope-tagged Kcnq2 mouse and mass spectrometry, we also demonstrated that KCNQ2 channels can associate with KCNQ5 channels in the absence of KCNQ3 channels in the brain. Thus, KCNQ2 channel composition is much more diverse than has been previously recognized, necessitating a re-examination of the genotype–phenotype relationship of KCNQ2 pathogenic variants.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Epilepsy,Autism Spectrum Disorder

SUBMITTER: Jeremy Balsbaugh  

LAB HEAD: Jeremy Balsbaugh

PROVIDER: PXD028142 | Pride | 2022-03-24

REPOSITORIES: Pride