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Specific serine proteases selectively damage KCNH2 (hERG1) potassium channels and I(Kr)
- Source :
- American journal of physiology. Heart and circulatory physiology. 290(3)
- Publication Year :
- 2005
-
Abstract
- KCNH2 ( hERG1) encodes the α-subunit proteins for the rapidly activating delayed rectifier K+ current ( IKr), a major K+ current for cardiac myocyte repolarization. In isolated myocytes IKr frequently is small in amplitude or absent, yet KCNH2 channels and IKr are targets for drug block or mutations to cause long QT syndrome. We hypothesized that KCNH2 channels and IKr are uniquely sensitive to enzymatic damage. To test this hypothesis, we studied heterologously expressed K+, Na+, and L-type Ca2+ channels, and in ventricular myoctyes IKr, slowly activating delayed rectifier K+ current ( IKs), and inward rectifier K+ current ( IK1), by using electrophysiological and biochemical methods. 1) Specific exogenous serine proteases (protease XIV, XXIV, or proteinase K) selectively degraded KCNH2 current ( IKCNH2) and its mature channel protein without damaging cell integrity and with minimal effects on the other channel currents; 2) immature KCNH2 channel protein remained intact; 3) smaller molecular mass KCNH2 degradation products appeared; 4) protease XXIV selectively abolished IKr; and 5) reculturing HEK-293 cells after protease exposure resulted in the gradual recovery of IKCNH2 and its mature channel protein over several hours. Thus the channel protein for IKCNH2 and IKr is uniquely sensitive to proteolysis. Analysis of the degradation products suggests selective proteolysis within the S5-pore extracellular linker, which is structurally unique among Kv channels. These data provide 1) a new mechanism to account for low IKr density in some isolated myocytes, 2) evidence that most complexly glycosylated KCNH2 channel protein is in the plasma membrane, and 3) new insight into the rate of biogenesis of KCNH2 channel protein within cells.
- Subjects :
- congenital, hereditary, and neonatal diseases and abnormalities
Proteases
ERG1 Potassium Channel
Physiology
Isolated myocytes
Membrane Potentials
Serine
Dogs
Physiology (medical)
Repolarization
Animals
Myocytes, Cardiac
Cells, Cultured
chemistry.chemical_classification
Chemistry
Cardiac myocyte
Serine Endopeptidases
Potassium channel
Ether-A-Go-Go Potassium Channels
Cell biology
Delayed rectifier
Enzyme
Biochemistry
Potassium
Cardiology and Cardiovascular Medicine
Ion Channel Gating
Subjects
Details
- ISSN :
- 03636135
- Volume :
- 290
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Accession number :
- edsair.doi.dedup.....c9f778f3720dafa431dbc52b415a336e