Calcium-activated potassium channels are proteins that are widely expressed on the surface of many cells types. One subtype, the KCa3.1 channel, is present on immune cells and cancer cells. Preclinical studies have shown that inhibiting KCa3.1 function reduces inflammation in experimental models of several diseases, including stroke, spinal cord injury, Alzheimer's disease and autoimmune disorders. Given the role of KCa3.1 in these diseases, it is important to understand how this channel is regulated.
A new article by TWRI Senior Scientist Dr. Lyanne Schlichter provides evidence that KCa3.1 function is inhibited by a signalling pathway that involves adenosine, cyclic AMP and cyclic AMP protein kinase (PKA). This is an important anti-inflammatory pathway that protects cells in the central nervous system, and elsewhere in the body, from injury.
Dr. Schlichter and her team used molecular biology and biochemistry techniques, as well as electrical and optical recordings, to study KCa3.1 function in microglia (immune cells that reside in the central nervous system). They discovered that the adenosine-PKA pathway inhibits KCa3.1 channel activity. This resulted in less calcium entry into the cells, an event that controls microglial activation. They verified the results by making a mutated version of the KCa3.1 channel that lacked the ability to interact with PKA. As expected, this modified channel was incapable of responding to the PKA signalling pathway.
Explains Dr. Schlichter; "Both PKA and the KCa3.1 channel are involved in a variety of human diseases. Although inhibiting KCa3.1 is beneficial in several disease models, its interaction with PKA was controversial until now. Our study shows that KCa3.1 is regulated by PKA, an interaction that might represent an important therapeutic target."
This work was supported by the Heart and Stroke Foundation and the Toronto General & Western Hospital Foundation.
PKA reduces the rat and human KCa3.1 current, CaM binding, and Ca2+ signaling, which requires Ser332/334 in the CaM-binding C terminus. Wong R, Schlichter LC. Journal of Neuroscience. 2014 Oct 1. [Pubmed abstract]
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