Connexin43 is involved in the effect of endothelin‐1 on astrocyte proliferation and glucose uptake

Abstract

In previous studies, we showed that endothelin-1 increased astrocyte proliferation and glucose uptake. These effects were similar to those observed with other gap junction inhibitors, such as carbenoxolone (CBX). Because 24-h treatment with endothelin-1 or CBX downregulates the expression of connexin43, the main protein forming astrocytic gap junctions, which can also be involved in proliferation, in this study, we addressed the possible role of connexin43 in the effects of endothelin-1. To do so, connexin43 was silenced in astrocytes by siRNA. The knock down of connexin43 increased the rate of glucose uptake, characterized by the upregulation of GLUT-1 and type I hexokinase. Neither endothelin-1 nor CBX were able to further increase the rate of glucose uptake in connexin43-silenced astrocytes. In agreement, no effects of endothelin-1 and CBX on GLUT-1 and type I hexokinase were observed in connexin-43 silenced astrocytes or in astrocytes from connexin43 knock-out (KO) mice. Our previous studies suggested a close relationship between glucose uptake and astrocyte proliferation. Consistent with this, connexin43-silenced astrocytes exhibited an increase in Ki-67, a marker of proliferation. The effects of ET-1 on retinoblastoma phosphorylation on Ser780 and on the upregulation of cyclins D1 and D3 were affected by the levels of connexin43. In conclusion, our results indicate that connexin43 participates in the effects of endothelin-1 on glucose uptake and proliferation in astrocytes. Interestingly, although the rate of growth in connexin43 KO astrocytes has been reported to be reduced, we observed that an acute reduction in connexin43 by siRNA increased proliferation and glucose uptake. V V C

Carbenoxolone Enhances TRAIL-Induced Apoptosis Through the Upregulation of Death Receptor 5 and Inhibition of Gap Junction Intercellular Communication in Human Glioma

“…CBX has been shown to inhibit GJ communication through its effect on Cx43 [29], which is the most abundant connexin molecules in the brain. Phosphorylation of Cx43 was shown to associate with closure of GJ channel [30].…”

Tumor necrosis factor-mediated downregulation of spinal astrocytic connexin43 leads to increased glutamatergic neurotransmission and neuropathic pain in mice

“…Gap junctions are formed by two connexins expressed in neighboring cells, which consist of a hexamer of connexin (Cx) proteins. Gap junctions have important functions including buffering extracellular Na + and K + , supplying sources of energy between neighboring cells, exchanging molecular substances and intercellular communication, passing signaling molecules such as glutamate, ATP and second messengers (Herrero-González et al, 2009;Langer et al, 2012;Saez et al, 2003;Steinhäuser et al, 2012). Several types of Cx, including Cx30, Cx36 and Cx43, have been identified in the spinal cord (Bautista et al, 2012;Nagy et al, 1999;Rash et al, 2001).…”

Connexin Channel-Dependent Signaling Pathways in Inflammation

“…The gap junction-coupled astrocytic network sustains thus the delivery of glucose or lactate and finally glutamatergic synaptic transmission of neurons [108]. From the vascular point of view, vasoactive molecules such as endothelins have been shown to block glucose trafficking via gap junctions and to increase astrocytic glucose uptake and proliferation [107,109]. …”