Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation

TY - JOUR

T1 - Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation

AU - Glasscock, Edward

AU - Voigt, Niels

AU - McCauley, Mark D

AU - Sun, Qiang

AU - Li, Na

AU - Chiang, David Y

AU - Zhou, Xiao-Bo

AU - Molina, Cristina E

AU - Thomas, Dierk

AU - Schmidt, Constanze

AU - Skapura, Darlene G

AU - Noebels, Jeffrey L

AU - Dobrev, Dobromir

AU - Wehrens, Xander H T

PY - 2015/9

Y1 - 2015/9

N2 - Voltage-gated Kv1.1 channels encoded by the Kcna1 gene are traditionally regarded as being neural-specific with no known expression or intrinsic functional role in the heart. However, recent studies in mice reveal low-level Kv1.1 expression in heart and cardiac abnormalities associated with Kv1.1-deficiency suggesting that the channel may have a previously unrecognized cardiac role. Therefore, this study tests the hypothesis that Kv1.1 channels are associated with arrhythmogenesis and contribute to intrinsic cardiac function. In intra-atrial burst pacing experiments, Kcna1-null mice exhibited increased susceptibility to atrial fibrillation (AF). The atria of Kcna1-null mice showed minimal Kv1 family ion channel remodeling and fibrosis as measured by qRT-PCR and Masson's trichrome histology, respectively. Using RT-PCR, immunocytochemistry, and immunoblotting, KCNA1 mRNA and protein were detected in isolated mouse cardiomyocytes and human atria for the first time. Patients with chronic AF (cAF) showed no changes in KCNA1 mRNA levels relative to controls; however, they exhibited increases in atrial Kv1.1 protein levels, not seen in paroxysmal AF patients. Patch-clamp recordings of isolated human atrial myocytes revealed significant dendrotoxin-K (DTX-K)-sensitive outward current components that were significantly increased in cAF patients, reflecting a contribution by Kv1.1 channels. The concomitant increases in Kv1.1 protein and DTX-K-sensitive currents in atria of cAF patients suggest that the channel contributes to the pathological mechanisms of persistent AF. These findings provide evidence of an intrinsic cardiac role of Kv1.1 channels and indicate that they may contribute to atrial repolarization and AF susceptibility.

AB - Voltage-gated Kv1.1 channels encoded by the Kcna1 gene are traditionally regarded as being neural-specific with no known expression or intrinsic functional role in the heart. However, recent studies in mice reveal low-level Kv1.1 expression in heart and cardiac abnormalities associated with Kv1.1-deficiency suggesting that the channel may have a previously unrecognized cardiac role. Therefore, this study tests the hypothesis that Kv1.1 channels are associated with arrhythmogenesis and contribute to intrinsic cardiac function. In intra-atrial burst pacing experiments, Kcna1-null mice exhibited increased susceptibility to atrial fibrillation (AF). The atria of Kcna1-null mice showed minimal Kv1 family ion channel remodeling and fibrosis as measured by qRT-PCR and Masson's trichrome histology, respectively. Using RT-PCR, immunocytochemistry, and immunoblotting, KCNA1 mRNA and protein were detected in isolated mouse cardiomyocytes and human atria for the first time. Patients with chronic AF (cAF) showed no changes in KCNA1 mRNA levels relative to controls; however, they exhibited increases in atrial Kv1.1 protein levels, not seen in paroxysmal AF patients. Patch-clamp recordings of isolated human atrial myocytes revealed significant dendrotoxin-K (DTX-K)-sensitive outward current components that were significantly increased in cAF patients, reflecting a contribution by Kv1.1 channels. The concomitant increases in Kv1.1 protein and DTX-K-sensitive currents in atria of cAF patients suggest that the channel contributes to the pathological mechanisms of persistent AF. These findings provide evidence of an intrinsic cardiac role of Kv1.1 channels and indicate that they may contribute to atrial repolarization and AF susceptibility.

KW - Aged

KW - Animals

KW - Atrial Fibrillation

KW - Female

KW - Heart Atria

KW - Humans

KW - Immunoblotting

KW - Immunohistochemistry

KW - Kv1.1 Potassium Channel

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Middle Aged

KW - Myocytes, Cardiac

KW - Patch-Clamp Techniques

KW - Real-Time Polymerase Chain Reaction

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1007/s00395-015-0505-6

DO - 10.1007/s00395-015-0505-6

M3 - SCORING: Journal article

C2 - 26162324

VL - 110

SP - 505

JO - BASIC RES CARDIOL

JF - BASIC RES CARDIOL

SN - 0300-8428

IS - 5

ER -