Novel regulators of Slo2 potassium channels

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Abstract The focus of research in my lab is to determine how physiological functions of Slo2 channels are regulated by other proteins. Slo2 channels are a family of large-conductance potassium channels existing in mammals as well as invertebrates. Human and mouse each have two such channels: Slo2.1/Slick and Slo2.2/Slack, whereas the nematode C. elegans has only one, SLO-2. These channels are widely expressed in the nervous system, and play important roles in shaping neuronal firing properties. Mutations of Slack in humans often cause epilepsies and intellectual disability. Although physiological functions of Slo2 channels are expected to be dependent on many other regulatory proteins, molecular identities and their mechanisms of action are only beginning to be recognized. In the past few years, we identified several proteins required for SLO-2 physiological functions in C. elegans, including two RNA/DNA binding proteins (HRPU-2 and a SAFB-like transcription modulator tentatively named SLTM-1), one RNA editing modulator (ADR-1), one protein tyrosine phosphatase (tentatively named PTP-5), and one pseudokinase (SCYL-1), which all have mammalian homologs. Our results suggest that HRPU-2 and SLTM-1 regulate SLO-2 function through controlling the expression of PTP-5, whereas ADR-1 regulates SLO-2 function through enhancing the expression of SCYL-1. We have demonstrated that SCYL-1 increases SLO-2 activity through direct interactions, and this regulation is conserved between mammalian SCYL1 and Slack. In the next five years, our major goals are to determine how PTP-5 regulates SLO-2 function and whether the regulatory mechanism is conserved with human Slo2 and a human PTP-5 homolog, to determine how HRPU-2 and SLTM-1 regulate PTP-5 expression, and to identify putative proteins required for ADR-1- dependent SCYL-1 expression using a forward genetics approach. We envision that results from the proposed studies will not only provide important new knowledge about the regulation of worm SLO-2, but also have the potential to reveal evolutionarily conserved mechanisms of Slo2 channel regulation.