Functional interaction with filamin A and intracellular Ca 2+ enhance the surface membrane expression of a small-conductance Ca 2+ -activated K + (SK2) channel

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 27; pp. 9989 - 9994
• Main Authors: Rafizadeh, Sassan, Zhang, Zheng, Woltz, Ryan L., Kim, Hyo Jeong, Myers, Richard E., Lu, Ling, Tuteja, Dipika, Singapuri, Anil, Bigdeli, Amir Ali Ziaei, Harchache, Sana Ben, Knowlton, Anne A., Yarov-Yarovoy, Vladimir, Yamoah, Ebenezer N., Chiamvimonvat, Nipavan
• Format: Journal Article
• Language: English
• Published: 08.07.2014
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1323541111

Significance The precise subcellular localization of ion channel proteins is necessary for the proper function of excitable cells. The trafficking of several ion channels is dependent on the interaction of the ion channel proteins with cytoskeletal proteins, underpinned by a number of diseases in which the defect lies with the interacting proteins. Here, we demonstrate the role of filamin A, a cytoskeletal protein, in augmenting the membrane expression of small-conductance, Ca 2+ -activated K + channels (K Ca 2.2 or SK2) in atrial myocytes. We further demonstrate that SK2 channel trafficking is Ca 2+ -dependent in the presence of another cytoskeletal protein, α-actinin2, thereby establishing the role of filamin A, α-actinin2, and intracellular Ca 2+ in trafficking of SK2 channels. The findings may have implications in other excitable cells. For an excitable cell to function properly, a precise number of ion channel proteins need to be trafficked to distinct locations on the cell surface membrane, through a network and anchoring activity of cytoskeletal proteins. Not surprisingly, mutations in anchoring proteins have profound effects on membrane excitability. Ca 2+ -activated K + channels (K Ca 2 or SK) have been shown to play critical roles in shaping the cardiac atrial action potential profile. Here, we demonstrate that filamin A, a cytoskeletal protein, augments the trafficking of SK2 channels in cardiac myocytes. The trafficking of SK2 channel is Ca 2+ -dependent. Further, the Ca 2+ dependence relies on another channel-interacting protein, α-actinin2, revealing a tight, yet intriguing, assembly of cytoskeletal proteins that orchestrate membrane expression of SK2 channels in cardiac myocytes. We assert that changes in SK channel trafficking would significantly alter atrial action potential and consequently atrial excitability. Identification of therapeutic targets to manipulate the subcellular localization of SK channels is likely to be clinically efficacious. The findings here may transcend the area of SK2 channel studies and may have implications not only in cardiac myocytes but in other types of excitable cells.