Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling.
Richard Z LinZhongju LuEvgeny P AnyukhovskyYa-Ping JiangHong Zhan WangJunyuan GaoMichael R RosenLisa M BallouIra S CohenPublished in: The Journal of general physiology (2019)
Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, cancer, and heart failure. Here, we show that inhibition of PI3K slows the pacing rate of the SN in situ and in vitro and reduces the early slope of diastolic depolarization. Furthermore, inhibition of PI3K causes a negative shift in the voltage dependence of activation of the pacemaker current, I F, while addition of its second messenger, phosphatidylinositol 3,4,5-trisphosphate, induces a positive shift. These shifts in the activation of I F are independent of, and larger than, those induced by the autonomic nervous system. These results suggest that PI3K is an important regulator of heart rate, and perturbations in this signaling pathway may contribute to the development of arrhythmias.
Keyphrases
- heart rate
- blood pressure
- heart rate variability
- left ventricular
- cardiac resynchronization therapy
- heart failure
- induced apoptosis
- protein kinase
- signaling pathway
- transcription factor
- type diabetes
- papillary thyroid
- cell cycle arrest
- cardiovascular disease
- pi k akt
- lymph node
- oxidative stress
- epithelial mesenchymal transition
- glycemic control
- squamous cell carcinoma
- atrial fibrillation
- metabolic syndrome
- squamous cell
- adipose tissue
- childhood cancer
- cell death
- acute heart failure
- young adults
- weight loss
- skeletal muscle