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Research ArticleTOXICOLOGY

The Molecular Mechanism of “Ryegrass Staggers,” a Neurological Disorder of K+ Channels

Wendy L. Imlach, Sarah C. Finch, James Dunlop, Andrea L. Meredith, Richard W. Aldrich and Julie E. Dalziel
Journal of Pharmacology and Experimental Therapeutics December 2008, 327 (3) 657-664; DOI: https://doi.org/10.1124/jpet.108.143933
Wendy L. Imlach
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Sarah C. Finch
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James Dunlop
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Andrea L. Meredith
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Richard W. Aldrich
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Julie E. Dalziel
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Abstract

“Ryegrass staggers” is a neurological condition of unknown mechanism that impairs motor function in livestock. It is caused by infection of perennial ryegrass pastures by an endophytic fungus that produces neurotoxins, predominantly the indole-diterpenoid compound lolitrem B. Animals grazing on such pastures develop uncontrollable tremors and become uncoordinated in their movement. Lolitrem B and the structurally related tremor inducer paxilline both act as potent large conductance calcium-activated potassium (BK) channel inhibitors. Using patch clamping, we show that their different apparent affinities correlate with their toxicity in vivo. To investigate whether the motor function deficits produced by lolitrem B and paxilline are due to inhibition of BK ion channels, their ability to induce tremor and ataxia in mice deficient in this ion channel (Kcnma1-/-) was examined. Our results show that mice lacking Kcnma1 are unaffected by these neurotoxins. Furthermore, doses of these substances known to be lethal to wild-type mice had no effect on Kcnma1-/- mice. These studies reveal the BK channel as the molecular target for the major components of the motor impairments induced by ryegrass neurotoxins. Unexpectedly, when the response to lolitrem B was examined in mice lacking the β4 BK channel accessory subunit (Kcnmb4-/-), only low-level ataxia was observed. Our study therefore reveals a new role for the accessory BK β4 subunit in motor control. The β4 subunit could be considered as a potential target for treatment of ataxic conditions in animals and in humans.

Footnotes

  • This work was supported by a Marsden Fund, Royal Society of New Zealand Grant AGR302 (to J.E.D., S.C.F., A.L.M., R.W.A.); the Howard Hughes Medical Institute (to R.W.A.); and a travel grant from the Neural Systems Research Theme, University of Otago, New Zealand (to W.L.I.). This work has been presented in abstract form in Imlach WL, Finch SC, Dunlop J, Meredith AL, Aldrich RW, and Dalziel JE (2007) Using neurotoxins to understand the role of BK channels in the brain. Biophys J Abstr 92:278a.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.143933.

  • ABBREVIATIONS: BK, large conductance calcium-activated potassium channel; hSlo, human BK channel pore-forming subunit; DMSO, dimethyl sulfoxide; HEK, human embryonic kidney.

  • ↵ Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ↵1 Current affiliation: Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, New York.

    • Received July 27, 2008.
    • Accepted September 17, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 3
1 Jun 2023
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Research ArticleTOXICOLOGY

The Molecular Mechanism of “Ryegrass Staggers,” a Neurological Disorder of K+ Channels

Wendy L. Imlach, Sarah C. Finch, James Dunlop, Andrea L. Meredith, Richard W. Aldrich and Julie E. Dalziel
Journal of Pharmacology and Experimental Therapeutics December 1, 2008, 327 (3) 657-664; DOI: https://doi.org/10.1124/jpet.108.143933

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Research ArticleTOXICOLOGY

The Molecular Mechanism of “Ryegrass Staggers,” a Neurological Disorder of K+ Channels

Wendy L. Imlach, Sarah C. Finch, James Dunlop, Andrea L. Meredith, Richard W. Aldrich and Julie E. Dalziel
Journal of Pharmacology and Experimental Therapeutics December 1, 2008, 327 (3) 657-664; DOI: https://doi.org/10.1124/jpet.108.143933
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