Molecular coupling of a Ca2+-activated K+ channel to L-type Ca2+ channels via alpha-actinin2.
Cytoskeletal proteins are known to sculpt the structural architecture of cells. However, their role as bridges linking the functional crosstalk of different ion channels is unknown. Here, we demonstrate that a small conductance Ca(2+)-activated K(+) channels (SK2 channel), present in a variety of cells, where they integrate changes in intracellular Ca(2+) concentration [Ca(2+)(i)] with changes in K(+) conductance and membrane potential, associate with L-type Ca(2+) channels; Ca(v)1.3 and Ca(v)1.2 through a physical bridge, alpha-actinin2 in cardiac myocytes. SK2 channels do not physically interact with L-type Ca(2+) channels, instead, the 2 channels colocalize via their interaction with alpha-actinin2 cytoskeletal protein. The association of SK2 channel with alpha-actinin2 localizes the channel to the entry of external Ca(2+) source, which regulate the channel function. Furthermore, we demonstrated that the functions of SK2 channels in atrial myocytes are critically dependent on the normal expression of Ca(v)1.3 Ca(2+) channels. Null deletion of Ca(v)1.3 channel results in abnormal function of SK2 channel and prolongation of repolarization and atrial arrhythmias. Our study provides insight into the molecular mechanisms of the coupling of SK2 channel with voltage-gated Ca(2+) channel, and represents the first report linking the coupling of 2 different types of ion channels via cytoskeletal proteins.
Lu
Ling
L
Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, One Shields Avenue, GBSF 6315, Davis, CA 95616, USA.
Zhang
Qian
Q
Timofeyev
Valeriy
V
Zhang
Zhao
Z
Young
J Nilas
JN
Shin
Hee-Sup
HS
Knowlton
Anne A
AA
Chiamvimonvat
Nipavan
N
D000185:Actinin / Q000378:metabolism*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000172:deficiency / Q000378:metabolism*; D002460:Cell Line; D004553:Electric Conductivity; D006325:Heart Atria; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism* / Q000502:physiology; D014018:Tissue Distribution; D020798:Two-Hybrid System Techniques
C401401:ACTN2 protein, human; C472073:CACNA1D protein, human; C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; C496897:KCNN2 protein, human; C496898:Kcnn2 protein, mouse; C419385:L-type calcium channel alpha(1C); D051640:Small-Conductance Calcium-Activated Potassium Channels; D000185:Actinin