TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes

• In contrast to previous studies we found a strong TASK-3 expression in human auricles.
• TASK-3 is localized at the plasma membrane of isolated cardiomyocytes.
• Single-channel recordings identified heteromeric channels formed by TASK-1 and TASK-3.
• Heteromeric TASK-1 and TASK-3 channels have a reduced affinity for TASK-1 blockers.
• Drug design against atrial fibrillation should consider potential TASK-3 heteromers.

TASK-1 channels have emerged as promising drug targets against atrial fibrillation, the most common arrhythmia in the elderly. While TASK-3, the closest relative of TASK-1, was previously not described in cardiac tissue, we found a very prominent expression of TASK-3 in right human auricles. Immunocytochemistry experiments of human right auricular cardiomyocytes showed that TASK-3 is primarily localized at the plasma membrane. Single-channel recordings of right human auricles in the cell-attached mode, using divalent-cation-free solutions, revealed a TASK-1-like channel with a single-channel conductance of about 30 pS. While homomeric TASK-3 channels were not found, we observed an intermediate single-channel conductance of about 55 pS, possibly reflecting the heteromeric channel formed by TASK-1 and TASK-3. Subsequent experiments with TASK-1/TASK-3 tandem channels or with co-expressed TASK-1 and TASK-3 channels in HEK293 cells or Xenopus oocytes, supported that the 55 pS channels observed in right auricles have electrophysiological characteristics of TASK-1/TASK-3 heteromers. In addition, co-expression experiments and single-channel recordings suggest that heteromeric TASK-1/TASK-3 channels have a predominant surface expression and a reduced affinity for TASK-1 blockers. In summary, the evidence for heteromeric TASK-1/TASK-3 channel complexes together with an altered pharmacologic response to TASK-1 blockers in vitro is likely to have further impact for studies isolating ITASK-1 from cardiomyocytes and for the development of drugs specifically targeting TASK-1 in atrial fibrillation treatment.