Phactr1 regulates Slack (KCNT1) channels via protein phosphatase 1 (PP1).

The Slack (KCNT1) gene encodes sodium-activated potassium channels that are abundantly expressed in the central nervous system. Human mutations alter the function of Slack channels, resulting in epilepsy and intellectual disability. Most of the disease-causing mutations are located in the extended cytoplasmic C-terminus of Slack channels and result in increased Slack current. Previous experiments have shown that the C-terminus of Slack channels binds a number of cytoplasmic signaling proteins. One of these is Phactr1, an actin-binding protein that recruits protein phosphatase 1 (PP1) to certain phosphoprotein substrates. Using co-immunoprecipitation, we found that Phactr1 is required to link the channels to actin. Using patch clamp recordings, we found that co-expression of Phactr1 with wild-type Slack channels reduces the current amplitude but has no effect on Slack channels in which a conserved PKC phosphorylation site (S407) that regulates the current amplitude has been mutated. Furthermore, a Phactr1 mutant that disrupts the binding of PP1 but not that of actin fails to alter Slack currents. Our data suggest that Phactr1 regulates the Slack by linking PP1 to the channel. Targeting Slack-Phactr1 interactions may therefore be helpful in developing the novel therapies for brain disorders associated with the malfunction of Slack channels. © 2019 Federation of American Societies for Experimental Biology.

Citation

Syed Rydwan Ali, Taylor Joseph Malone, Yalan Zhang, Magdalena Prechova, Leonard Konrad Kaczmarek. Phactr1 regulates Slack (KCNT1) channels via protein phosphatase 1 (PP1). FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Jan;34(1):1591-1601

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PMID: 31914597

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