Cardiac deficiency of P21-activated kinase 1 promotes atrial arrhythmogenesis in mice following adrenergic challenge.

P21-activated kinase 1 (Pak1) signalling plays a vital and overall protective role in the heart. However, the phenotypes of deficiency in the cardiac atria have not been well explored. In this study, cardiac-conditional knock-out (cKO) mice were studied under baseline and adrenergic challenge conditions. cKO mice show atrial arrhythmias including atrial fibrillation (AF) , detected during anaesthetized electrocardiography without evidence of interstitial fibrosis upon Masson's trichrome staining. Optical mapping of left atrial preparations from cKO mice revealed a higher incidence of Ca and action potential alternans under isoprenaline challenge and differences in baseline action potential and calcium transient characteristics. Type-2 ryanodine receptor (RyR2) channels from cKO hearts had a higher open probability than those from wild-type. Reverse transcription-quantitative polymerase chain reaction and Western blotting indicated that pCamkII and RyR2 are highly phosphorylated at baseline in the atria of cKO mice, while the expression of and as a Na-Ca exchanger, controlling the influx of Ca from outside of the cell and efflux of Na from the cytoplasm, are augmented. Chromatin immunoprecipitation study showed that pCreb1 interacts with and . Our study thus demonstrates that deficiency of promotes atrial arrhythmogenesis under adrenergic stress, probably through post-translational and transcriptional modifications of key molecules that are critical to Ca homeostasis. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.