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A novel leg-shaking Drosophila mutant defective in a voltage-gated K(+)current and hypersensitive to reactive oxygen species.

Authors
Type
Published Article
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Publication Date
Volume
20
Issue
16
Pages
5958–5964
Identifiers
PMID: 10934243
Source
Medline

Abstract

1,1'-Dimethyl-4,4'-bipyridinium dichloride (methyl viologen; paraquat), an herbicide that causes depletion of NADPH and generates excessive reactive oxygen species (ROS) in vivo, has been used to screen for ROS-sensitive Drosophila mutants. One mutant so isolated, named quiver(1) (qvr(1)), has a leg-shaking phenotype. Mutants of the Shaker (Sh), Hyperkinetic (Hk), and ether a go-go (eag) genes, which encode different K(+) channel subunits that regulate the A-type K(+) current (I(A)) in different ways, exhibit leg shaking under ether anesthesia and have heightened metabolic rates and shortened life spans. We found that Sh, Hk, and eag mutant flies were all hypersensitive to paraquat. Double-mutant combinations among the three channel mutations and qvr(1) had drastically enhanced sensitivity to paraquat. Synaptic transmission at the larval neuromuscular junction was increased in the qvr(1) mutant to the level of Sh mutants. Similar to eag Sh double mutants, double mutants of eag and qvr(1) showed striking enhancement in synaptic transmission and a wings-down phenotype, the hallmarks of extreme hyperexcitability. Voltage-clamp experiments demonstrated that the qvr(1) mutation specifically disrupted the Sh-dependent I(A) current without altering the other currents [I(K), Ca(2+)-activated fast (I(CF)) and slow (I(CS)) currents, and I(Ca)] in larval muscles. Several deficiency strains of the qvr locus failed to complement qvr(1) and confirmed that ether-induced leg shaking, reduced I(A) current, and paraquat hypersensitivity map to the same locus. Our results suggest that the qvr gene may encode a novel K(+) channel-related polypeptide and indicate a strong link between a voltage-activated K(+) current and vulnerability to ROS.

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