Kir2.1 inward rectifier K+ channels are regulated independently by protein kinases and ATP hydrolysis

Fakler, Bernd; Brändle, Uwe; Glowatzki, Elisabeth; Zenner, Hans‐Peter; Ruppersberg, J. P.

doi:10.1016/0896-6273(94)90426-x

Cited by 138 publications

(114 citation statements)

References 31 publications

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“…Fakler et al 20 found a PKC-dependent inhibition and PKA-dependent increase of the mouse inward rectifier IRK 1 initially cloned by Kubo et al 6 Likewise, the PMA-dependent run-up of current in all combined mutations of PKC-phosphorylation sites in our study might be explained by a putative PMAdependent activation of resting PKA-sites.…”

Section: Discussionmentioning

confidence: 55%

Human Cardiac Inwardly-Rectifying K ⁺ Channel Kir _2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

et al. 2002

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Background-Protein kinases A (PKA) and C (PKC) are activated in ischemic preconditioning and heart failure, conditions in which patients develop arrhythmias. The native inward rectifier potassium current (IK 1 ) plays a central role in the stabilization of the resting membrane potential and the process of arrhythmogenesis. This study investigates the functional relationship between PKC and IK 1 . Methods and Results-In whole-cell patch-clamp experiments with isolated human atrial cardiomyocytes, the IK 1 was reduced by 41% when the nonspecific activator of PKC phorbol 12 myristate 13-acetate (PMA; 100 nmol/L) was applied. To investigate the effects of PKC on cloned channel underlying parts of the native IK 1 , we expressed Kir 2.1b heterologously in Xenopus oocytes and measured currents with the double-electrode voltage-clamp technique. PMA decreased the current by an average of 68%, with an IC 50 of 0.68 nmol/L. The inactive compound 4-␣-PMA was ineffective. Thymeleatoxin and 1-oleolyl-2-acetyl-sn-glycerol, 2 specific activators of PKC, produced effects similar to those of PMA. Inhibitors of PKC, ie, staurosporine and chelerytrine, could inhibit the PMA effect (1 nmol/L) significantly. After mutation of the PKC phosphorylation sites (especially S64A and T353A), PMA became ineffective. Conclusions-The human IK 1 in atrial cardiomyocytes and one of its underlying ion channels, the Kir 2.1b channel, is inhibited by PKC-dependent signal transduction pathways, possibly contributing to arrhythmogenesis in patients with structural heart disease in which PKC is activated. Key Words: ion channels Ⅲ signal transduction Ⅲ arrhythmia Ⅲ electrophysiology I n human cardiomyocytes, repolarization at the end of the action potential is caused by many different potassium currents, which can be classified as delayed outward and inward rectifiers. The inward rectifier potassium current (IK 1 ) reveals inwardly rectifying properties responsible for the terminal repolarization at the end of the cardiac action potential. The native IK 1 is composed of several different potassium channels with distinct single channel conductances of 20 pS, 35 pS and 10 pS. 1 Likewise, different gene families (Kir 2.1 , Kir 2.2 , and Kir 2.3 ) have been found in human heart encoding IK 1 . 2 The native IK 1 may be involved in arrhythmogenesis of coronary artery disease 3 and dilated cardiomyopathy. 4 Mutations of Kir 2.1 channels are associated with Anderson's syndrome, an inherited disease with an arrhythmia characterized by QT-prolongation, periodic paralysis, and dysmorphic features. 5 Within the Kir 2.1 family, several distinct channels have been cloned in chronological order. The first channel, named IRK 1 or MM-IRK 1 , was found in mouse tissue. 6 The rabbit channel RBHIK 1 revealed a 97% amino acid homology to MM-IRK 1 . 7 The human HH-IRK 1 , which has a 98% homology to MM-IRK 1 , was the first channel cloned from the human heart. 8 With the help of primers derived from IRK 1 , 2 channel sequences were identified in human atrial tissue; one was...

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Section: Discussionmentioning

confidence: 55%

Human Cardiac Inwardly-Rectifying K ⁺ Channel Kir _2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

et al. 2002

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“…current in cholinergic neurons of basal nucleus, which raises excitability of the neurons [13][14][15]. Because both intracellular ATP and phosphorylation were reported to be essential to maintain IRK1 channel activity [16], IRKs can be targets of protein kinases and phosphatases. Actually localization of calmodulin-dependent adenylyl cyclase in the brain are quite similar to that of IRK2 mRNA [17].…”

Section: Discussionmentioning

confidence: 99%

Differential distribution of classical inwardly rectifying potassium channel mRNAs in the brain: comparison of IRK2 with IRK1 and IRK3

et al. 1996

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Distribution of IRK2 inwardly rectifying potassium channel mRNA in the mouse brain was studied using in situ hybridization histochemistry and compared with those of other classical inwardly rectifying potassium channel (IRK1 and IRK3) mRNAs. All these IRK channel mRNAs were detected in neurons, but not in glial cells. Their distribution patterns in the brain were, however, quite divergent: IRK2 mRNA was detected extremely high in granule cells of cerebellum, relatively high in motor trigeminai nucleus and moderate in olfactory bulb, piriform cortex, cerebral cortex, CA1 through CA3 regions of hippocampus, dentate gyrus and pontine nucleus. On the other hand, IRK1 mRNA was expressed throughout whole brain but in particular subsets of neurons, and IRK3 mRNA was in forebrain. Expression of these three IRK mRNAs overlapped in hippocampus, olfactory bulb, and cerebral cortex. This differential distribution of IRK mRNAs suggests that each of these channels has its specific function in regulation of the excitability of brain neurons.

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“…The two-microelectrode voltage clamp configuration was used to record currents from Xenopus laevis oocytes. In several sets of experiments oocytes were individually injected with cRNA encoding each of the K + channels rat I~K [1], rat Kvl.l [14] or rat Kir2.1 [15]. Recordings were performed at 22°C using a Geneclamp amplifier (Axon Instruments, Foster City, CA, USA) and MacLab D/A converter and software for data acquisition and analysis (ADInstruments, Castle Hill, Australia).…”

Section: Electrophysiological Experiments In Xenopus Oocytesmentioning

confidence: 99%

Specific blockade of slowly activating I_sK channels by chromanols — impact on the role of I_sK channels in epithelia

et al. 1996

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Chromanols, which were recently shown to inhibit cAMP-mediated CI secretion in colon crypts via a blockade of a cAMP-activated K + conductance, were analyzed for their effects on distinct cloned K + channels expressed in Xenopus oocytes. The lead chromanol 293B specifically inhibited I~K channels with an ICs0 of 7 pmol/1 without affecting the delayed rectifier Kvl.1 or the inward rectifier Kir2.1. Moreover, several other chromanols displayed the same rank order of potency for Isx inhibition as demonstrated in colon crypts. Finally, we tested the effects of the previously described I~K blocker azimilide on cAMP mediated CI secretion in rat colon crypts. Similar to 293B azimilide inhibited the forskolin induced CI-secretion. These data suggest that Isx protein induced K + conductances are the targets for the chromanol 293B and its analogues, and azimilide.

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Kir2.1 inward rectifier K+ channels are regulated independently by protein kinases and ATP hydrolysis

Cited by 138 publications

References 31 publications

Human Cardiac Inwardly-Rectifying K ⁺ Channel Kir _2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

Human Cardiac Inwardly-Rectifying K ⁺ Channel Kir _2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

Differential distribution of classical inwardly rectifying potassium channel mRNAs in the brain: comparison of IRK2 with IRK1 and IRK3

Specific blockade of slowly activating I_sK channels by chromanols — impact on the role of I_sK channels in epithelia

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Kir2.1 inward rectifier K+ channels are regulated independently by protein kinases and ATP hydrolysis

Cited by 138 publications

References 31 publications

Human Cardiac Inwardly-Rectifying K + Channel Kir 2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

Human Cardiac Inwardly-Rectifying K + Channel Kir 2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

Differential distribution of classical inwardly rectifying potassium channel mRNAs in the brain: comparison of IRK2 with IRK1 and IRK3

Specific blockade of slowly activating IsK channels by chromanols — impact on the role of IsK channels in epithelia

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Human Cardiac Inwardly-Rectifying K ⁺ Channel Kir _2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

Human Cardiac Inwardly-Rectifying K ⁺ Channel Kir _2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

Specific blockade of slowly activating I_sK channels by chromanols — impact on the role of I_sK channels in epithelia