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TOXICOLOGY

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

AgResearch, Grasslands Research Centre, Palmerston North, New Zealand (W.L.I., J.D., J.E.D.); Ruakura Research Centre, Hamilton, New Zealand (S.C.F.); Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland (A.L.M.); and Section of Neurobiology, Center for Learning and Memory, The University of Texas at Austin, Texas (R.W.A.)

"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.

Address correspondence to: Dr. Julie Dalziel, AgResearch, Grasslands Research Centre, Tennent Dr., Private Bag 11008, Palmerston North 4442, New Zealand. E-mail: julie.dalziel{at}agresearch.co.nz