A Switch Mechanism for Gβγ Activation of IKACh

Medina, Igor; Krapivinsky, Grigory; Arnold, Susanne; Kovoor, Pramesh; Krapivinsky, Luba; Clapham, David E.

doi:10.1074/jbc.m004989200

Cited by 56 publications

(72 citation statements)

References 25 publications

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“…In July 2011, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.5 days. Studies suggest that agonist-independent I KAch activation requires ATP, [7][8][9] pointing to the potential involvement of PKs. Indirect evidence suggests that in AF patients, the isoform of protein kinase C (PKC) may contribute to I KAChC activation.…”

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confidence: 99%

Differential Protein Kinase C Isoform Regulation and Increased Constitutive Activity of Acetylcholine-Regulated Potassium Channels in Atrial Remodeling

Makary

Voigt

Maguy

et al. 2011

Circulation Research

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Key Words: atrial tachycardia Ⅲ protein kinase C isoforms Ⅲ remodeling A trial fibrillation (AF), the most common sustained cardiac arrhythmia, leads to atrial tachycardia-induced remodeling (ATR) that promotes AF (AF begets AF). 1 Atrial cardiomyocytes from chronic AF patients or atrialtachypaced dogs exhibit an agonist-independent inward rectifier K ϩ current with properties of the muscarinic cholinoceptor-activated K ϩ current I KACh . [2][3][4][5] Inhibition of this constitutive current (I KAChC ) with the selective Kir3 channel blocker tertiapin reverses ATR-induced action potential duration abbreviation and AF promotion. 3,4 Enhanced inward rectifier currents are particularly effective in stabilizing and accelerating atrial rotors because, in addition to reducing action potential duration, they hyperpolarize atrial cardiomyocytes and remove voltagedependent I Na inactivation. 6 The molecular basis of ATR-induced I KACh activation is poorly understood. Increased receptor-independent dissociation of G␣ and G␤␥ subunits does not appear to be involved. 3 Original received July 20, 2011; revision received August 18, 2011; accepted August 25, 2011. In July 2011, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.5 days.From Studies suggest that agonist-independent I KAch activation requires ATP, 7-9 pointing to the potential involvement of PKs. Indirect evidence suggests that in AF patients, the isoform of protein kinase C (PKC) may contribute to I KAChC activation. 10 The present study aimed to investigate the molecular basis of ATR-induced I KAChC channel activation in a dog model. Methods Animal ModelA total of 100 mongrel dogs (20 -36 kg) were divided into control and ATR groups (including both preliminary studies and work presented in the article). Animal care procedures followed National Institutes of Health guidelines (publication 85-23, revised 1996) and were approved by the Animal Research Ethics Committee of the Montreal Heart Institute. The animal model was prepared as previously described in detail. 11 Briefly, the atrioventricular node was ablated by radiofrequency-application. The right ventricle was paced at 80 bpm and the right atrium was paced at 400 bpm for 7 days. Open chest study was performed as previously described. 12 On study days, dogs were anesthetized (morphine 2 mg ⅐ kg Ϫ1 subcutaneous, ␣-chloralose 120 mg ⅐ kg Ϫ1 intravenous load, 29.25 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 infusion) and mechanically ventilated. Right atrial effective refractory period was measured at basic cycle lengths of 150, 200, 250, 300, and 360 ms with 10 basic stimuli (S1) and a second stimulus (S2) with 5-ms decrements (all pulses twice-threshold, 2 ms). AF (irregular atrial rhythm Ͼ400 bpm) was induced with 1-to 10-second atrial burst pacing (10 -20 Hz, 4ϫthreshold, 2-ms pulses).Mean AF duration was determined in each dog based on 10 AF inductions for AF Ͻ5 minutes and five inductions for 5 to 30 minutes of AF. AF Ͼ30 minutes was considered sustained; c...

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Differential Protein Kinase C Isoform Regulation and Increased Constitutive Activity of Acetylcholine-Regulated Potassium Channels in Atrial Remodeling

Makary

Voigt

Maguy

et al. 2011

Circulation Research

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“…Release of acetylcholine following vagal stimulation leads to activation of the cardiac muscarinic receptors. K ir 3.1/ K ir 3.4 channels play an important role in the sinoatrial node, where an increased K ϩ conductance will give rise to a slower depolarization of the pacemaker potential and a reduction of the heart rate (281,358). Furthermore, K ir 3.1/K ir 3.4 channels are important for atrial repolarization.…”

Section: Phasementioning

confidence: 99%

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Schmitt

Grunnet

Olesen

2014

Physiological Reviews

194

197

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About 10 distinct potassium channels in the heart are involved in shaping the action potential. Some of the K+ channels are primarily responsible for early repolarization, whereas others drive late repolarization and still others are open throughout the cardiac cycle. Three main K+ channels drive the late repolarization of the ventricle with some redundancy, and in atria this repolarization reserve is supplemented by the fairly atrial-specific KV1.5, Kir3, KCa, and K2P channels. The role of the latter two subtypes in atria is currently being clarified, and several findings indicate that they could constitute targets for new pharmacological treatment of atrial fibrillation. The interplay between the different K+ channel subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in disease states such as atrial fibrillation or heart failure. The underlying posttranscriptional and posttranslational remodeling of the individual K+ channels changes their activity and significance relative to each other, and they must be viewed together to understand their role in keeping a stable heart rhythm, also under menacing conditions like attacks of reentry arrhythmia.

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“…Consistent with this idea, recent publications have shown that in atrial myocardium Kir3.1 forms a macromolecular complex, allowing for local regulation of I K,ACh function. 28,29 The atrial GIRK1 macromolecular complex is composed of the catalytic subunits of PKA, PKC, and CaMKII and the protein phosphatases PP1 and PP2A. 28,29 Thus, the qualitative and quantitative composition of the GIRK1 macromolecular complex may change during AF, resulting in abnormal regulation of I K,ACh .…”

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confidence: 99%

The G Protein–Gated Potassium Current I _K,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation

et al. 2005

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Background— The molecular mechanism of increased background inward rectifier current ( I K1 ) in atrial fibrillation (AF) is not fully understood. We tested whether constitutively active acetylcholine (ACh)-activated I K,ACh contributes to enhanced basal conductance in chronic AF (cAF). Methods and Results— Whole-cell and single-channel currents were measured with standard voltage-clamp techniques in atrial myocytes from patients with sinus rhythm (SR) and cAF. The selective I K,ACh blocker tertiapin was used for inhibition of I K,ACh . Whole-cell basal current was larger in cAF than in SR, whereas carbachol (CCh)-activated I K,ACh was lower in cAF than in SR. Tertiapin (0.1 to 100 nmol/L) reduced I K,ACh in a concentration-dependent manner with greater potency in cAF than in SR (−logIC 50 : 9.1 versus 8.2; P <0.05). Basal current contained a tertiapin-sensitive component that was larger in cAF than in SR (tertiapin [10 nmol/L]-sensitive current at −100 mV: cAF, −6.7±1.2 pA/pF, n=16/5 [myocytes/patients] versus SR, −1.7±0.5 pA/pF, n=24/8), suggesting contribution of constitutively active I K,ACh to basal current. In single-channel recordings, constitutively active I K,ACh was prominent in cAF but not in SR (channel open probability: cAF, 5.4±0.7%, n=19/9 versus SR, 0.1±0.05%, n=16/9; P <0.05). Moreover, I K1 channel open probability was higher in cAF than in SR (13.4±0.4%, n=19/9 versus 11.4±0.7%, n=16/9; P <0.05) without changes in other channel characteristics. Conclusions— Our results demonstrate that larger basal inward rectifier K + current in cAF consists of increased I K1 activity and constitutively active I K,ACh . Blockade of I K,ACh may represent a new therapeutic target in AF.

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A Switch Mechanism for Gβγ Activation of IKACh

Cited by 56 publications

References 25 publications

Differential Protein Kinase C Isoform Regulation and Increased Constitutive Activity of Acetylcholine-Regulated Potassium Channels in Atrial Remodeling

Differential Protein Kinase C Isoform Regulation and Increased Constitutive Activity of Acetylcholine-Regulated Potassium Channels in Atrial Remodeling

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

The G Protein–Gated Potassium Current I _K,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation

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A Switch Mechanism for Gβγ Activation of IKACh

Cited by 56 publications

References 25 publications

Differential Protein Kinase C Isoform Regulation and Increased Constitutive Activity of Acetylcholine-Regulated Potassium Channels in Atrial Remodeling

Differential Protein Kinase C Isoform Regulation and Increased Constitutive Activity of Acetylcholine-Regulated Potassium Channels in Atrial Remodeling

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

The G Protein–Gated Potassium Current I K,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation

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The G Protein–Gated Potassium Current I _K,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation