J Neurogastroenterol Motil.  2023 Apr;29(2):250-261. 10.5056/jnm22052.

Protein Kinase CK2 Modulates the Calcium Sensitivity of Type 3 Small-conductance Calcium-activated Potassium Channels in Colonic Platelet-derived Growth Factor Receptor Alpha-positive Cells From Streptozotocin-induced Diabetic Mice

• Song NN
• Huang X
• Lu HL
• Lu C
• Chen J
• Xu WX

• KMID: 2541577
• DOI: http://doi.org/10.5056/jnm22052

Abstract

Background/Aims
The gastrointestinal symptom of diabetes mellitus, chronic constipation, seriously affects patients’ life. Whereas, the mechanism of chronic constipation is still ambiguous, resulting in a lack of effective therapies for this symptom. As a part of the smooth muscle cells, interstitial cells of Cajal, and platelet-derived growth factor receptor alpha-positive (PDGFRα⁺ ) cells syncytium (SIP syncytium), PDGFRα⁺ cells play an important role in regulating colonic motility. According to our previous study, in PDGFRα⁺cells in colons of diabetic mice, the function of the P2Y1 purinergic receptor/type 3 small-conductance calcium-activated potassium (SK3) channel signaling pathway is strengthened, which may lead to colonic dysmotility. The purpose of this study is to investigate the changes in SK3 channel properties of PDGFRα⁺ cells in diabetic mice.
Methods
Whole-cell patch clamp, Western blotting, superoxide dismutase activity measurement, and malondialdehyde measurement were main methods in the present study.
Results
The present study revealed that when dialysed with low calcium ion (Ca 2⁺ ) solution, the SK3 current density was significantly decreased in PDGFRα⁺ cells from diabetic mice. However, the SK3 current density in PDGFRα⁺ cells was enhanced from diabetic mice when dialysed with high Ca 2⁺ solution. Moreover, hydrogen peroxide-treatment mimicked this phenomenon in SK3 transgenic HEK293 cells. The subunit of SK3 channels, protein kinase CK2, was up-regulated in colonic muscle layers and hydrogen peroxidetreated HEK293 cells. Additionally, protein phosphatase 2A, the subunit of SK3 channels, was not changed in streptozotocin-treated mouse colons or hydrogen peroxide-treated HEK293 cells.
Conclusion
The diabetic oxidative stress-induced upregulation of CK2 contributed to modulating SK3 channel sensitivity to Ca 2⁺ in colonic PDGFRα⁺ cells, which may result in colonic dysmotility in diabetic mice.

Keyword

Constipation; Diabetes mellitus; Potassium channels; calcium-activated; Protein kinase CK2