Cardiac small conductance Ca2+-activated K+ channel subunits form heteromultimers via the coiled-coil domains in the C termini of the channels

Dipika Tuteja, Sassan Rafizadeh, Valeriy Timofeyev, Shuyun Wang, Zheng Zhang, Ning Li, Robertino K. Mateo, Anil Singapuri, J Nilas Young, Anne A Knowlton, Nipavan Chiamvimonvat

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Rationale: Ca2+-activated K+ channels are present in a wide variety of cells. We have previously reported the presence of small conductance Ca2+-activated K+ (SK or KCa) 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. Methods and 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 Ca2+-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.

Original languageEnglish (US)
Pages (from-to)851-859
Number of pages9
JournalCirculation Research
Volume107
Issue number7
DOIs
StatePublished - Oct 1 2010

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Calcium-Activated Potassium Channels
Muscle Cells
Protein Isoforms
Cardiac Myocytes
Action Potentials
Ligands
Peptides
Therapeutics

Keywords

  • Ca-activated K channels
  • cardiac myocytes
  • coiled-coil domains
  • heteromultimerization

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Cardiac small conductance Ca2+-activated K+ channel subunits form heteromultimers via the coiled-coil domains in the C termini of the channels. / Tuteja, Dipika; Rafizadeh, Sassan; Timofeyev, Valeriy; Wang, Shuyun; Zhang, Zheng; Li, Ning; Mateo, Robertino K.; Singapuri, Anil; Young, J Nilas; Knowlton, Anne A; Chiamvimonvat, Nipavan.

In: Circulation Research, Vol. 107, No. 7, 01.10.2010, p. 851-859.

Research output: Contribution to journalArticle

Tuteja, Dipika ; Rafizadeh, Sassan ; Timofeyev, Valeriy ; Wang, Shuyun ; Zhang, Zheng ; Li, Ning ; Mateo, Robertino K. ; Singapuri, Anil ; Young, J Nilas ; Knowlton, Anne A ; Chiamvimonvat, Nipavan. / Cardiac small conductance Ca2+-activated K+ channel subunits form heteromultimers via the coiled-coil domains in the C termini of the channels. In: Circulation Research. 2010 ; Vol. 107, No. 7. pp. 851-859.
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AU - Tuteja, Dipika

AU - Rafizadeh, Sassan

AU - Timofeyev, Valeriy

AU - Wang, Shuyun

AU - Zhang, Zheng

AU - Li, Ning

AU - Mateo, Robertino K.

AU - Singapuri, Anil

AU - Young, J Nilas

AU - Knowlton, Anne A

AU - Chiamvimonvat, Nipavan

PY - 2010/10/1

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N2 - Rationale: Ca2+-activated K+ channels are present in a wide variety of cells. We have previously reported the presence of small conductance Ca2+-activated K+ (SK or KCa) 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. Methods and 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 Ca2+-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.

AB - Rationale: Ca2+-activated K+ channels are present in a wide variety of cells. We have previously reported the presence of small conductance Ca2+-activated K+ (SK or KCa) 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. Methods and 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 Ca2+-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.

KW - Ca-activated K channels

KW - cardiac myocytes

KW - coiled-coil domains

KW - heteromultimerization

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