ER stress modulates Kv1.5 channels via PERK branch in HL-1 atrial myocytes: Relevance to atrial arrhythmogenesis and the effect of tetramethylpyrazine

Endoplasmic reticulum (ER) stress is implicated in cardiac arrhythmia whereas the associated mechanisms remain inadequately understood. Kv1.5 channels are essential for atrial repolarization. Whether ER stress affects Kv1.5 channels is unknown. This study aimed to elucidate the response of Kv1.5 channels to ER stress by clarifying the unfolded protein response (UPR) branch responsible for the channel modulation. In addition, the effect of tetramethylpyrazine (TMP) on Kv1.5 channels was studied. Patch clamp and western-blot results revealed that exposure of HL-1 atrial myocytes to ER stress inducer tunicamycin upregulates Kv1.5 expression, increases Kv1.5 channel current (<i>I</i> _<i>Kur</i> ) (14.91 ± 1.11 <i>vs.</i> 6.11 ± 1.31 pA/pF, <i>P</i> < 0.001), and shortened action potential duration (APD) (APD₉₀: 82.79 ± 5.25 <i>vs</i>.121.11 ± 6.72 ms, <i>P</i> < 0.01), which could be reverted by ER stress inhibitors. Blockade of the PERK branch while not IRE1 and ATF6 branches of UPR downregulated Kv1.5 expression, accompanied by a decreased <i>I</i> _<i>Kur</i> (9.03 ± 0.99 pA/pF) and a prolonged APD₉₀ (113.69 ± 4.41 ms) (<i>P</i> < 0.01). PERK-mediated increases of Kv1.5 expression and <i>I</i> _<i>Kur</i> were also observed in HL-1 cells incubated with thapsigargin. TMP suppressed the enhancement of <i>I</i> _<i>Kur</i> (10.52 ± 0.97 <i>vs.</i> 17.52 ± 2.25 pA/pF, <i>P</i> < 0.05), prevented the shortening of APD (APD₉₀: 110.16 ± 5.36 <i>vs.</i> 84.84 ± 4.58 ms, <i>P</i> < 0.05), and inhibited the upregulation of Kv1.5 triggered by ER stress. Our study suggests that ER stress induces upregulation and activation of Kv1.5 channels in atrial myocytes through the PERK branch of UPR. TMP prevents Kv1.5 upregulation/activation and the resultant APD shortening by inhibiting ER stress. These results may shed light on the mechanisms of atrial arrhythmogenesis and the antiarrhythmic effect of the traditional Chinese herb TMP.