Environmental and pathophysiological challenges, such as oxidative stress, infection, and excessive neural activation, disrupt the functions of excitable cells and thus threaten the health and survival of animals. These challenges lead to the accumulation of misfolded and aggregated proteins in the endoplasmic reticulum (ER), a condition referred to as ER stress. ER stress is closely associated with cellular calcium ions; excessive cytosolic calcium ions disrupt ER calcium homeostasis and result in ER stress, while ER stress causes calcium leak from the ER and in turn calcium accumulation in the cytoplasm and mitochondria. Excessive calcium accumulation can lead to the activation of apoptotic factors and calcium-dependent proteases. Thus, it is critical that excitable cells have a protective mechanism that antagonizes calcium increases. The BK SLO-1 channel is a calcium-activated potassium channel that has been described as an ?emergency brake? that responds to excessive depolarization and accumulation of intracellular calcium ions. A critical factor that influences BK channel function is its density at the plasma membrane. Indeed, changes in BK channel density affect disease course or symptoms in an increasing number of disease conditions and drug use disorders, including autism, Alzheimer's disease, and alcohol abuse. Despite the importance of BK channel density, three key processes that determine BK channel density, channel trafficking, recycling, and degradation, are poorly understood. By implementing a C. elegans forward genetic screen designed to identify genes responsible for BK channel trafficking and recycling, we have identified three novel genes that influence the trafficking of BK channels. In this proposal, we will molecularly characterize these genes and how these genes contribute to BK channel trafficking in the basal and stress conditions. Our proposed study will improve our understanding of the pathological mechanisms for diseases that are associated with BK channel dysfunction, and provide therapeutic opportunities to selectively modulate BK channel density by altering the activities of proteins that mediate channel trafficking and recycling.

Public Health Relevance

The BK channel is a calcium-activated potassium channel that is critical for the regulation of calcium-mediated processes, including neuronal communication and muscle activation. The function or level of BK channels influences disease course or symptoms in a growing number of diseases, including epilepsy, autism, and ataxia. Our study on BK channel trafficking and recycling will provide therapeutic opportunities to selectively modulate the level of BK channels.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM125749-01
Application #
9422967
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Faupel-Badger, Jessica
Project Start
2018-01-01
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Rosalind Franklin University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064