Novel regulators of Slo2 potassium channels

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.

Grant Number: 5R35GM139620-06
NIH Institute/Center: NIH
Principal Investigator: Bojun Chen