Editorial Comment to Platelet‐derived growth factor‐BB increases expression of connexin 43 in an extracellular‐regulated protein kinase‐dependent manner in bladder smooth muscle cells

Abstract

Connexin 43 (Cx43) is the best-characterized gap junction protein in rat and human bladder smooth muscle cells, as well as myofibroblasts beneath the urothelium. Although Cx43 expression in the normal bladder is usually low in detrusor muscle, it increases after partial bladder outlet obstruction in rats and in patients with detrusor overactivity (DO). Negoro et al. also reported that circadian oscillation of Cx43 is associated with the biological clock and contributes to diurnal changes in bladder capacity. Therefore, a gap junction protein has a key role in communicating between cells and an autonomous bladder activity. This article shows the myogenic mechanism of DO involving platelet-derived growth factor-BB (PDGF-BB), Cx43 and signaling pathway, such as extracellular-regulated protein kinase (ERK), c-jun amino-terminal kinase (JNK) and 38 mitogen-activated protein kinase. The new finding of this study is that PDGF-BB upregulates Cx43 expression through the activation of ERK and platelet-derived growth factor receptor-b (PDGFR-b) signaling pathways in vitro. The authors concluded that the inhibition of mitogenactivated protein kinase (MAPK)/ERK signaling pathway provides a potential target to manipulate DO. The purpose of this might be very useful, and the conclusions drawn are interesting. However, it is still unlikely to be possible to consider ERK inhibitors as candidates of DO treatment, because MAPK/ERK signaling extensively functions on cell growth and regulation. Interestingly, Ikeda et al. reported that coordinated spontaneous activity requires gap junction upregulation in urothelial cells and lamina propria myofibroblasts. It has been also reported that T-type calcium channel subtypes are confirmed to colocalize in interstitial cells of Cajal in rat bladders, which participates in the spontaneous activity of interstitial cells of Cajal and phasic contractions of the bladder by modulating in interstitial cells of Cajal. These mechanisms are complex and still far from well known. However, if it is fact that PDGF-BB positively regulates Cx43 expression, PDGF signaling might be associated with spontaneous bladder activity involving interstitial cells of Cajal. The authors should examine the network mechanisms of spontaneous bladder activity involving ERK, PDGFR-b signaling, gap junction proteins and c-kit positive pacemaker cells (Cajal) in future studies. These new findings might contribute to elucidate the genesis of DO and pharmacological target in OAB patients.