RT Journal Article SR Electronic T1 HRPU-2, a homologue of mammalian hnRNP U, regulates synaptic transmission by controlling the expression of SLO-2 potassium channel in C. elegans JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 1991-17 DO 10.1523/JNEUROSCI.1991-17.2017 A1 Ping Liu A1 Sijie Jason Wang A1 Zhao-Wen Wang A1 Bojun Chen YR 2017 UL http://www.jneurosci.org/content/early/2017/12/07/JNEUROSCI.1991-17.2017.abstract AB Slo2 channels are large-conductance potassium channels abundantly expressed in the nervous system. However, it is unclear how their expression level in neurons is regulated. Here we report that HRPU-2, an RNA-binding protein homologous to mammalian hnRNP U, plays an important role in regulating the expression of SLO-2 (a homologue of mammalian Slo2) in C. elegans. Loss-of-function (lf) mutants of hrpu-2 were isolated in a genetic screen for suppressors of a sluggish phenotype caused by a hyperactive SLO-2. In hrpu-2(lf) mutants, SLO-2-mediated delayed outward currents in neurons are greatly decreased, and neuromuscular synaptic transmission is enhanced. These mutant phenotypes can be rescued by expressing wild-type HRPU-2 in neurons. HRPU-2 binds to slo-2 mRNA, and hrpu-2(lf) mutants show decreased SLO-2 protein expression. In contrast, hrpu-2(lf) does not alter the expression of either the BK channel SLO-1 or the Shaker type potassium channel SHK-1. hrpu-2(lf) mutants are indistinguishable from wild type in gross motor neuron morphology and locomotion behavior. Taken together, these observations suggest that HRPU-2 plays important roles in SLO-2 function by regulating SLO-2 protein expression, and that SLO-2 is likely among a restricted set of proteins regulated by HRPU-2. Mutations of human Slo2 channel and hnRNP U are strongly linked to epileptic disorders and intellectual disability. The findings of this study suggest a potential link between these two molecules in human patients.SIGNIFICANCE STATEMENThnRNP U belongs to a family of RNA-binding proteins that play important roles in controlling gene expression. Recent studies have established a strong link between mutations of hnRNP U and human epilepsies and intellectual disability. However, it is unclear how mutations of hnRNP U may cause such disorders. This study shows that mutations of HRPU-2, a worm homologue of mammalian hnRNP U, result in dysfunction of a Slo2 potassium channel, which is critical to neuronal function. Because mutations of Slo2 channels are also strongly associated with epileptic encephalopathies and intellectual disability in humans, findings of this study point to a potential mechanism underlying neurological disorders caused by hnRNP U mutations.