+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein



Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein



Cardiovascular Research 59(1): 14-26



Objective: Patients with HERG-associated long QT syndrome typically develop tachyarrhythmias during physical or emotional stress. Previous studies have revealed that activation of the beta-adrenergic system and consecutive elevation of the intracellular cAMP concentration regulate HERG channels via protein kinase A-mediated phosphorylation of the channel protein and via direct interaction with the cAMP binding site of HERG. In contrast, the influence of the alpha-adrenergic signal transduction cascade on HERG currents as suggested by recent reports is less well understood. The aim of the present study was to elucidate the biochemical pathways of the protein kinase C (PKC)-dependent regulation of HERG currents. Methods: HERG channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. Results: Application of the phorbol ester PMA, an unspecific protein kinase activator, shifted the voltage dependence of HERG activation towards more positive potentials. This effect could be mimicked by activation of conventional PKC isoforms with thymeleatoxin. Coexpression of HERG with the beta-subunits minK or hMiRP1 did not alter the effect of PMA. Specific inhibition of PKC abolished the PMA-induced activation shift, suggesting that PKC is required within the regulatory mechanism. The PMA-induced effect could still be observed when the PKC-dependent phosphorylation sites in HERG were deleted by mutagenesis. Cytoskeletal proteins such as actin filaments or microtubules did not affect the HERG activation shift. Conclusion: In addition to the known effects of PKA and cAMP, HERG channels are also modulated by PKC. The molecular mechanisms of this PKC-dependent process are not completely understood but do not depend on direct PKC-dependent phosphorylation of the channel.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 011266813

Download citation: RISBibTeXText

PMID: 12829172

DOI: 10.1016/s0008-6363(03)00386-9


Related references

Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A. Journal of Biological Chemistry 274(39): 27457-27462, 1999

Deletion of protein kinase A phosphorylation sites in the cardiac HERG potassium channel inhibits current suppression and activation shift by protein kinase A. Circulation 100(18 Suppl. ): I 633, 1999

Regulation of the cardiac repolarizing HERG potassium channel by protein kinase A. Trends in Cardiovascular Medicine 10(5): 205-209, 2000

Regulation of the HERG potassium channel activation kinetics by protein kinases. Circulation 98(17 Suppl. ): I126, 1998

Regulation of surface localization of the small conductance Ca2+-activated potassium channel, Sk2, through direct phosphorylation by cAMP-dependent protein kinase. Journal of Biological Chemistry 281(17): 11769-11779, 2006

Mechanisms underlying the protein-kinase mediated regulation of the HERG potassium channel synthesis. Biochimica et Biophysica Acta 1823(8): 1273-1284, 2012

Regulation of Surface Localization of the Small Conductance Ca superscript 2+-activated Potassium Channel, Sk2, through Direct Phosphorylation by cAMP-dependent Protein Kinase. Journal of biological chemistry28 281(17): 11769-11779, 2006

HERG potassium channel activation is shifted by phorbol esters via protein kinase A-dependent pathways. Journal of Biological Chemistry 273(39): 25285-25291, 1998

Phosphorylation of the A-kinase-anchoring protein Yotiao contributes to protein kinase A regulation of a heart potassium channel. Journal of Biological Chemistry 280(36): 31347-31352, 2005

Molecular mechanisms for cAMP-independent activation of MaxiK channel: G protein direct channel regulation and contribution to the tuning of vascular smooth muscle tone. Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica 122 Suppl: 37p-39p, 2003

AMP-activated protein kinase regulates hERG potassium channel. Pflugers Archiv 465(11): 1573-1582, 2013

Direct phosphorylation of l type calcium channel by magnesium atp and cyclic amp dependent protein kinase reverses channel activity run down. Circulation 82(4 Suppl. 3): III343, 1990

Anchoring protein AKAP79-mediated PKA phosphorylation of STIM1 determines selective activation of the ARC channel, a store-independent Orai channel. Journal of Physiology 593(3): 559-572, 2015

Src Kinase Is the Connecting Player between Protein Kinase A (PKA) Activation and Hyperpolarization through SLO3 Potassium Channel Regulation in Mouse Sperm. Journal of Biological Chemistry 290(30): 18855-18864, 2015

Regulation of ATP-sensitive potassium channel function by protein kinase A-mediated phosphorylation in transfected HEK293 cells. Embo Journal 19(5): 942-955, 2000