Src family protein tyrosine kinases modulate L-type calcium current in human atrial myocytes

Smooth muscle contraction involves regulating myosin light chain phosphorylation and dephosphorylation by myosin light chain kinase and myosin light chain phosphatase. C-kinase potentiated protein phosphatase-1 inhibitor of 17 kDa (CPI-17) and myosin phosphatase targeting subunit of myosin light-chain phosphatase (MYPT1) are crucial for regulating gastrointestinal smooth muscle contraction by inhibiting myosin light chain phosphatase. Integrin signalling involves the dynamic recruitment of several proteins, including focal adhesion kinase (FAK), to focal adhesions. FAK tyrosine kinase activation is involved in cell adhesion to the extracellular matrix via integrin signalling. FAK participates in linking the force generated by myofilament activation to the extracellular matrix and throughout the smooth muscle tissue. Here, we show that cholinergic stimulation activates FAK in gastric fundus smooth muscles. Electrical field stimulation in the presence of N -nitro-l-arginine methyl ester and MRS2500 contracted gastric fundus smooth muscle strips and increased FAK Y397 phosphorylation (pY397). Atropine blocked the contractions and prevented the increase in pY397. The FAK inhibitor PF-431396 inhibited the contractions and the increase in pY397. PF-431396 also inhibited the electrical field stimulation-induced increase in CPI-17 T38 phosphorylation, and reduced MYPT1 T696 and T853, and myosin light chain S19 phosphorylation. Ca influx was unaffected by PF-431396. Nicardipine inhibited the contractions but had no effect on the increase in pY397. Phorbol 12,13-dibutyrate or calyculin A contracted gastric fundus smooth muscle strips Ca independently and increased pY397. Our findings suggest that FAK is activated by mechanical forces during contraction and reveal a novel role of FAK in the regulation of CPI-17 phosphorylation.

show abstract

“…; Bogdelis et al . ). In addition, it is not uncommon for kinase inhibitors to have off‐target effects on ion channels (Son et al .…”

Section: Discussionmentioning

confidence: 97%

A role for focal adhesion kinase in facilitating the contractile responses of murine gastric fundus smooth muscles

Xie

Han

Grainger

et al. 2018

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…Src functions in multiple cellular processes, and participates in the occurrence of AF. Previous studies have indicated that inhibition of Src can increase I Ca,L in human atrial myocytes, suggesting that I Ca,L can be decreased by Src kinase in atrial myocytes ( 29 , 30 ). A previous study by our group also suggested that Src was involved in the decrease in I Ca,L in atrial myocytes under conditions of high hydrostatic pressure (HHP) at 40 mmHg ( 31 ).…”

Section: Introductionmentioning

confidence: 95%

Piezo1 Participated in Decreased L-Type Calcium Current Induced by High Hydrostatic Pressure via. CaM/Src/Pitx2 Activation in Atrial Myocytes

Yuan

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Hypertension is a major cardiovascular risk factor for atrial fibrillation (AF) worldwide. However, the role of mechanical stress caused by hypertension on downregulating the L-type calcium current (ICa,L), which is vital for AF occurrence, remains unclear. Therefore, the aim of the present study was to investigate the role of Piezo1, a mechanically activated ion channel, in the decrease of ICa,L in response to high hydrostatic pressure (HHP, one of the principal mechanical stresses) at 40 mmHg, and to elucidate the underlying pathways. Experiments were conducted using left atrial appendages from patients with AF, spontaneously hypertensive rats (SHRs) treated with valsartan (Val) at 30 mg/kg/day and atrium-derived HL-1 cells exposed to HHP. The protein expression levels of Piezo1, Calmodulin (CaM), and Src increased, while that of the L-type calcium channel a1c subunit protein (Cav1.2) decreased in the left atrial tissue of AF patients and SHRs. SHRs were more vulnerable to AF, with decreased ICa,L and shortened action potential duration, which were ameliorated by Val treatment. Validation of these results in HL-1 cells in the context of HHP also demonstrated that Piezo1 is required for the decrease of ICa,L by regulating Ca2+ transient and activating CaM/Src pathway to increase the expression of paired like homeodomain-2 (Pitx2) in atrial myocytes. Together, these data demonstrate that HHP stimulation increases AF susceptibility through Piezo1 activation, which is required for the decrease of ICa,Lvia. the CaM/Src/Pitx2 pathway in atrial myocytes.

show abstract

“…It is well known that phosphorylation of calcium channels is important for the function. Previous studies have shown that L type calcium channel could be regulated by tyrosine kinase src ( 36 – 38 ). According to our previous findings, EphB/ephrinB signaling in retina could interact with src ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Calcium channels are involved in EphB/ephrinB reverse signaling‑induced apoptosis in a rat chronic ocular hypertension model

et al. 2017

View full text Add to dashboard Cite

Erythropoietin-producing hepatocyte receptor B (EphB)/ephrinB reverse signaling has been revealed to be activated in chronic ocular hypertension (COH) by increasing the apoptosis of retinal ganglion cells (RGCs). However, the exact mechanism is not well understood. The present study investigated the involvement of Ca2+ channels in the apoptosis of RGCs induced by EphB/ephrinB reverse signaling in a rat CHO model, which was established by cauterizing 3 out of the 4 episcleral veins. The expression levels of four voltage-gated Ca2+ channel subunits (Cav3.1–3.3 and Cav1.2) were detected using immunofluorescence and western blot analysis. TUNEL staining was performed to assess RGC apoptosis following an injection with the T type Ca2+ channel blocker. Ca2+ channels, mainly the T type, were upregulated in COH rat retinas when compared with the sham group (P<0.01). Additionally, the Cav3.2 subunit of T type calcium channels was predominantly expressed in Müller cells and RGCs, such as ephrinB2. Furthermore, an intravitreal injection of the Ca2+ channel blocker Mibefradil (3 µM) reduced EphB2-fragment crystallizable region-induced RGC apoptosis in normal rats. Thus, the results suggest that Ca2+ channels in a COH model may be a pathway involved in ephrinB/EphB signaling-induced RGC apoptosis.

show abstract

Src family protein tyrosine kinases modulate L-type calcium current in human atrial myocytes

Cited by 7 publications

References 34 publications

A role for focal adhesion kinase in facilitating the contractile responses of murine gastric fundus smooth muscles

A role for focal adhesion kinase in facilitating the contractile responses of murine gastric fundus smooth muscles

Piezo1 Participated in Decreased L-Type Calcium Current Induced by High Hydrostatic Pressure via. CaM/Src/Pitx2 Activation in Atrial Myocytes

Calcium channels are involved in EphB/ephrinB reverse signaling‑induced apoptosis in a rat chronic ocular hypertension model

Contact Info

Product

Resources

About