SLEEPLESS, a Ly-6/neurotoxin family member, regulates the levels, localization and activity of Shaker

Mark N. Wu; William J. Joiner; Terry Dean; Zhifeng Yue; Corinne J. Smith; Dechun Chen; Toshinori Hoshi; Amita Sehgal; Kyunghee Koh

doi:10.1038/nn.2454

SLEEPLESS, a Ly-6/neurotoxin family member, regulates the levels, localization and activity of Shaker

Mark N. Wu, William J. Joiner, Terry Dean, Zhifeng Yue, Corinne J. Smith, Dechun Chen, Toshinori Hoshi, Amita Sehgal, Kyunghee Koh

School of Medicine

Research output: Contribution to journal › Article › peer-review

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Abstract

Sleep is a whole-organism phenomenon accompanied by global changes in neural activity. We previously identified SLEEPLESS (SSS) as a glycosylphosphatidyl inositol-anchored protein required for sleep in Drosophila. Here we found that SSS is critical for regulating the sleep-modulating potassium channel Shaker. SSS and Shaker shared similar expression patterns in the brain and specifically affected each other's expression levels. sleepless (sss) loss-of-function mutants exhibited altered Shaker localization, reduced Shaker current density and slower Shaker current kinetics. Transgenic expression of sss in sss mutants rescued defects in Shaker expression and activity cell-autonomously and suggested that SSS functions in wake-promoting, cholinergic neurons. In heterologous cells, SSS accelerated the kinetics of Shaker currents and was co-immunoprecipitated with Shaker, suggesting that SSS modulates Shaker activity via a direct interaction. SSS is predicted to belong to the Ly-6/neurotoxin superfamily, suggesting a mechanism for regulation of neuronal excitability by endogenous toxin-like molecules.

Original language	English (US)
Pages (from-to)	69-75
Number of pages	7
Journal	Nature neuroscience
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/nn.2454
State	Published - Jan 17 2010

ASJC Scopus subject areas

General Neuroscience

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@article{f358c808a1a54fecb8f05cad0ff12aed,

title = "SLEEPLESS, a Ly-6/neurotoxin family member, regulates the levels, localization and activity of Shaker",

abstract = "Sleep is a whole-organism phenomenon accompanied by global changes in neural activity. We previously identified SLEEPLESS (SSS) as a glycosylphosphatidyl inositol-anchored protein required for sleep in Drosophila. Here we found that SSS is critical for regulating the sleep-modulating potassium channel Shaker. SSS and Shaker shared similar expression patterns in the brain and specifically affected each other's expression levels. sleepless (sss) loss-of-function mutants exhibited altered Shaker localization, reduced Shaker current density and slower Shaker current kinetics. Transgenic expression of sss in sss mutants rescued defects in Shaker expression and activity cell-autonomously and suggested that SSS functions in wake-promoting, cholinergic neurons. In heterologous cells, SSS accelerated the kinetics of Shaker currents and was co-immunoprecipitated with Shaker, suggesting that SSS modulates Shaker activity via a direct interaction. SSS is predicted to belong to the Ly-6/neurotoxin superfamily, suggesting a mechanism for regulation of neuronal excitability by endogenous toxin-like molecules.",

author = "Wu, {Mark N.} and Joiner, {William J.} and Terry Dean and Zhifeng Yue and Smith, {Corinne J.} and Dechun Chen and Toshinori Hoshi and Amita Sehgal and Kyunghee Koh",

note = "Funding Information: We thank I. Levitan, J. Simpson, D. Bushey, B. Ganetzky, E. Rulifson, K. Kume, G. Korge and the Bloomington Stock Center for providing antibodies and fly stocks. We are grateful to T. Ferguson for help with oocyte preparation and M. Sowcik and R. Xu for technical assistance. This work was funded by a Burroughs-Wellcome Fund Career Award for Medical Scientists (M.N.W.), grants from the US National Institutes of Health (K08NS059671 to M.N.W., T32HL007953 to A. Pack, who supported T.D., R01GM057654 and R01GM078579 to T.H., P01AG017628 to A.S. and K.K., and R01GM088221 to K.K.), and a University Research Foundation Award from the University of Pennsylvania (K.K.). A.S. is an Investigator of the Howard Hughes Medical Institute.",

year = "2010",

month = jan,

day = "17",

doi = "10.1038/nn.2454",

language = "English (US)",

volume = "13",

pages = "69--75",

journal = "Nature neuroscience",

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T1 - SLEEPLESS, a Ly-6/neurotoxin family member, regulates the levels, localization and activity of Shaker

AU - Wu, Mark N.

AU - Joiner, William J.

AU - Dean, Terry

AU - Yue, Zhifeng

AU - Smith, Corinne J.

AU - Chen, Dechun

AU - Hoshi, Toshinori

AU - Sehgal, Amita

AU - Koh, Kyunghee

N1 - Funding Information: We thank I. Levitan, J. Simpson, D. Bushey, B. Ganetzky, E. Rulifson, K. Kume, G. Korge and the Bloomington Stock Center for providing antibodies and fly stocks. We are grateful to T. Ferguson for help with oocyte preparation and M. Sowcik and R. Xu for technical assistance. This work was funded by a Burroughs-Wellcome Fund Career Award for Medical Scientists (M.N.W.), grants from the US National Institutes of Health (K08NS059671 to M.N.W., T32HL007953 to A. Pack, who supported T.D., R01GM057654 and R01GM078579 to T.H., P01AG017628 to A.S. and K.K., and R01GM088221 to K.K.), and a University Research Foundation Award from the University of Pennsylvania (K.K.). A.S. is an Investigator of the Howard Hughes Medical Institute.

PY - 2010/1/17

Y1 - 2010/1/17

N2 - Sleep is a whole-organism phenomenon accompanied by global changes in neural activity. We previously identified SLEEPLESS (SSS) as a glycosylphosphatidyl inositol-anchored protein required for sleep in Drosophila. Here we found that SSS is critical for regulating the sleep-modulating potassium channel Shaker. SSS and Shaker shared similar expression patterns in the brain and specifically affected each other's expression levels. sleepless (sss) loss-of-function mutants exhibited altered Shaker localization, reduced Shaker current density and slower Shaker current kinetics. Transgenic expression of sss in sss mutants rescued defects in Shaker expression and activity cell-autonomously and suggested that SSS functions in wake-promoting, cholinergic neurons. In heterologous cells, SSS accelerated the kinetics of Shaker currents and was co-immunoprecipitated with Shaker, suggesting that SSS modulates Shaker activity via a direct interaction. SSS is predicted to belong to the Ly-6/neurotoxin superfamily, suggesting a mechanism for regulation of neuronal excitability by endogenous toxin-like molecules.

AB - Sleep is a whole-organism phenomenon accompanied by global changes in neural activity. We previously identified SLEEPLESS (SSS) as a glycosylphosphatidyl inositol-anchored protein required for sleep in Drosophila. Here we found that SSS is critical for regulating the sleep-modulating potassium channel Shaker. SSS and Shaker shared similar expression patterns in the brain and specifically affected each other's expression levels. sleepless (sss) loss-of-function mutants exhibited altered Shaker localization, reduced Shaker current density and slower Shaker current kinetics. Transgenic expression of sss in sss mutants rescued defects in Shaker expression and activity cell-autonomously and suggested that SSS functions in wake-promoting, cholinergic neurons. In heterologous cells, SSS accelerated the kinetics of Shaker currents and was co-immunoprecipitated with Shaker, suggesting that SSS modulates Shaker activity via a direct interaction. SSS is predicted to belong to the Ly-6/neurotoxin superfamily, suggesting a mechanism for regulation of neuronal excitability by endogenous toxin-like molecules.

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DO - 10.1038/nn.2454

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JO - Nature neuroscience

JF - Nature neuroscience

IS - 1

ER -

SLEEPLESS, a Ly-6/neurotoxin family member, regulates the levels, localization and activity of Shaker

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