The ability of animals to detect sensory stimulation, generate appropriate motor responses, and adapt detection mechanisms to changes in stimuli is crucial for survival. All of this signaling depends on the coordinated action of ion channels in the membranes of neurons. For example, there are Na+ channels specially evolved to carry out the fast depolarization of the neuronal membrane, as well as a wide range of K+ channels that subsequently repolarize the membrane and shape the action potential (AP) output of a neuron. In the proposed studies, the PI will test the role of KNa/slo2 channels, whose molecular identity has, relatively speaking, only recently been described. KNa/slo2 channels are Na+-activated K+ channels, which may have evolved to provide a protective ?brake? on membrane depolarization when neurons are over-stimulated. Although a neuroprotective role against over-excitation and a physiological role in sensory transduction/adaptation have been suggested, these role(s) of KNa/slo2 channels remain controversial. The PI proposes to use Drosophila as an in vivo model to address questions about how Na+ activates KNa/slo2 channels to affect neuronal signaling and behavior. The studies will look directly at AP firing and neuronal excitability, and explore behavioral effects on responsiveness to touch stimulation. Finally, the studies will use hyper-excitable genetic mutants with enhanced Na+ currents to test whether KNa/dslo2 channels are indeed able to counter over-excitation. 1

Public Health Relevance

In the proposed studies, the PI will test the role of KNa/slo2 channels, whose molecular identity has, relatively speaking, only recently been described. KNa/slo2 channels are Na+-activated K+ channels, which may have evolved to provide a protective ?brake? on membrane depolarization when neurons are over- stimulated. Although a neuroprotective role against over-excitation and a physiological role in sensory transduction/adaptation have been suggested, these role(s) of KNa/slo2 channels remain controversial. The PI proposes to use Drosophila as an in vivo model to investigate KNa/slo2 channels, and their Na+ sensitivity, in these potential roles. The studies will look directly at neuronal signaling and behavioral roles in the responsiveness to touch stimulation. Finally, the studies will use hyper-excitable genetic mutants, with seizure-like behavior, to test whether KNa/dslo2 channels are indeed able to counter over-excitation. If KNa/slo2 channels can indeed act as a neuroprotective mechanism for hyper-excitation, they may also provide a valuable therapeutic target for controlling hyperactivity in pathological conditions. 1

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Research Grants (R03)
Project #
5R03NS109495-02
Application #
9774328
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Churn, Severn Borden
Project Start
2018-09-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523