Cardiac small conductance Ca2+-activated K+ channel subunits form heteromultimers via the coiled-coil domains in the C termini of the channels.
BACKGROUND
Ca(2+)-activated K(+) channels are present in a wide variety of cells. We have previously reported the presence of small conductance Ca(2+)-activated K(+) (SK or K(Ca)) channels in human and mouse cardiac myocytes that contribute functionally toward the shape and duration of cardiac action potentials. Three isoforms of SK channel subunits (SK1, SK2, and SK3) are found to be expressed. Moreover, there is differential expression with more abundant SK channels in the atria and pacemaking tissues compared with the ventricles. SK channels are proposed to be assembled as tetramers similar to other K(+) channels, but the molecular determinants driving their subunit interaction and assembly are not defined in cardiac tissues.


OBJECTIVE
To investigate the heteromultimeric formation and the domain necessary for the assembly of 3 SK channel subunits (SK1, SK2, and SK3) into complexes in human and mouse hearts.


RESULTS
Here, we provide evidence to support the formation of heteromultimeric complexes among different SK channel subunits in native cardiac tissues. SK1, SK2, and SK3 subunits contain coiled-coil domains (CCDs) in the C termini. In vitro interaction assay supports the direct interaction between CCDs of the channel subunits. Moreover, specific inhibitory peptides derived from CCDs block the Ca(2+)-activated K(+) current in atrial myocytes, which is important for cardiac repolarization.


CONCLUSIONS
The data provide evidence for the formation of heteromultimeric complexes among different SK channel subunits in atrial myocytes. Because SK channels are predominantly expressed in atrial myocytes, specific ligands of the different isoforms of SK channel subunits may offer a unique therapeutic opportunity to directly modify atrial cells without interfering with ventricular myocytes.
Tuteja
Dipika
D
Department of Medicine, University of California, Davis, CA 95616, USA.
Rafizadeh
Sassan
S
Timofeyev
Valeriy
V
Wang
Shuyun
S
Zhang
Zheng
Z
Li
Ning
N
Mateo
Robertino K
RK
Singapuri
Anil
A
Young
J Nilas
JN
Knowlton
Anne A
AA
Chiamvimonvat
Nipavan
N
D000200:Action Potentials / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D006325:Heart Atria / Q000166:cytology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D014162:Transfection
C496894:KCNN1 protein, human; C496897:KCNN2 protein, human; C406328:KCNN3 protein, human; C496895:Kcnn1 protein, mouse; C496898:Kcnn2 protein, mouse; C496900:Kcnn3 protein, mouse; D051640:Small-Conductance Calcium-Activated Potassium Channels; D011188:Potassium