The molecular mechanism of "ryegrass staggers," a neurological disorder of K+ channels

Imlach, Wendy L., Finch, Sarah C., Dunlop, James, Meredith, Andrea L., Aldrich, Richard W. and Dalziel, Julie E. (2008) The molecular mechanism of "ryegrass staggers," a neurological disorder of K+ channels. Journal of Pharmacology and Experimental Therapeutics, 327 3: 657-664. doi:10.1124/jpet.108.143933


Author Imlach, Wendy L.
Finch, Sarah C.
Dunlop, James
Meredith, Andrea L.
Aldrich, Richard W.
Dalziel, Julie E.
Title The molecular mechanism of "ryegrass staggers," a neurological disorder of K+ channels
Journal name Journal of Pharmacology and Experimental Therapeutics   Check publisher's open access policy
ISSN 0022-3565
Publication date 2008-12
Sub-type Article (original research)
DOI 10.1124/jpet.108.143933
Volume 327
Issue 3
Start page 657
End page 664
Total pages 8
Place of publication Bethesda, MD, United States
Publisher American Society for Pharmacology and Experimental Therapeutics
Language eng
Formatted 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. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.
Keyword Activated Potassium Channels
Large-Conductance
Lolitrem-B
Beta-Subunit
Tremorgenic Neurotoxins
Structure Elucidation
Calcium
Cloning
Modulation
Mycotoxins
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
ERA 2012 Admin Only
 
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