© 1998 American Heart Association, Inc.
Original Contributions |
Independent and Exclusive Modulation of Cardiac Delayed Rectifying K+ Current by Protein Kinase C and Protein Kinase A
From Wyeth-Ayerst Research, Princeton, NJ.
Correspondence to Dr Randal Numann, Wyeth-Ayerst Research, CN8000, Princeton, NJ 08543-8000. E-mail numannr{at}war.wyeth.com
Abstract—Expression of minK in
Xenopus oocytes results in a current similar to the
cardiac slow delayed rectifying K+
(IKs) current. Modulation of the
IKs current in cardiac myocytes has been
studied extensively because of its role in shaping the cardiac action
potential. The human and cat minK cDNA have been cloned, but their
regulation by protein kinases has not been characterized. We report
here on the complex modulation of human and cat
IKs currents by protein kinase C (PKC) and
protein kinase A (PKA). Activation of PKC by phorbol ester (100 nmol/L
phorbol 12,13-didecanoate [PDD]) produces an increase in
IKs current that peaks after 20 minutes and
then subsequently decreases to 
50% of the control level after 1
hour. PKA activation only produces a sustained increase in
IKs current. Interestingly, premodulation by
PKC prevents IKs current modulation by PKA,
and PKC has no effect on IKs current after
potentiation by PKA. This shows that the IKs
current is modulated by PKC and PKA in a mutually exclusive manner and
suggests that multiple interacting phosphorylation
sites are involved. Activation of PKC by diacylglycerol analogues only
produces a slow decrease in IKs current. The
biphasic effects of PKC on IKs current
activated by PDD can also be separated by dose and duration.
Low doses of PDD (5 nmol/L) or brief applications (5 minutes) of 100
nmol/L PDD only produces IKs current
activation. These data suggest that there are at least 2 independent
PKC phosphorylation sites in the minK-KvLQT1 channel.
Additionally, long-term activation of PKC strongly attenuates the
IKs current expression even when the
corresponding changes in capacitance are taken into account.
Key Words: minK current • IKs • phosphorylation • protein kinase C • protein kinase A • Xenopus oocyte
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