title: Functional interaction with filamin A and intracellular Ca2+ enhance the surface membrane expression of a small-conductance Ca2+-activated K+ (SK2) channel.
abstract: 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 (KCa2 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.
authors.affiliation: Division of Cardiovascular Medicine.
authors.forename: Sassan
authors.initials: S
authors.lastname: Rafizadeh
authors.affiliation: Division of Cardiovascular Medicine.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Cardiovascular Medicine.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Woltz
authors.affiliation: Center for Neuroscience, and.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Division of Cardiovascular Medicine.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Myers
authors.affiliation: Division of Cardiovascular Medicine,Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Center for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing 210046, China; and.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Division of Cardiovascular Medicine.
authors.forename: Dipika
authors.initials: D
authors.lastname: Tuteja
authors.affiliation: Division of Cardiovascular Medicine.
authors.forename: Anil
authors.initials: A
authors.lastname: Singapuri
authors.affiliation: Division of Cardiovascular Medicine.
authors.forename: Amir Ali Ziaei
authors.initials: AA
authors.lastname: Bigdeli
authors.affiliation: Division of Cardiovascular Medicine.
authors.forename: Sana Ben
authors.initials: SB
authors.lastname: Harchache
authors.affiliation: Division of Cardiovascular Medicine,Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655.
authors.forename: Anne A
authors.initials: AA
authors.lastname: Knowlton
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, CA 95616;
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.affiliation: Center for Neuroscience, and.
authors.forename: Ebenezer N
authors.initials: EN
authors.lastname: Yamoah
authors.affiliation: Division of Cardiovascular Medicine,Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655 nchiamvimonvat@ucdavis.edu.
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
mesh_terms: D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D064448:Filamins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006325:Heart Atria / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*
chemical_list: D064448:Filamins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051640:Small-Conductance Calcium-Activated Potassium Channels; D002118:Calcium
keywords: atrial fibrillation; atrial myocytes; ion channel trafficking