Downregulation of gap junction expression and function by endoplasmic reticulum stress.
Gap junctional intercellular communication (GJIC) plays a critical role in the control of multiple cell behavior as well as in the maintenance of tissue and organ homeostasis. However, mechanisms involved in the regulation of gap junctions (GJs) have not been fully understood. Given endoplasmic reticulum (ER) stress and dysfunction of GJs coexist in several pathological situations, we asked whether GJs could be regulated by ER stress. Incubation of mesangial cells with ER stress-inducing agents (thapsigargin, tunicamycin, and AB(5) subtilase cytotoxin) resulted in a decrease in connexin 43 (Cx43) expression at both protein and mRNA levels. This was accompanied by a loss of GJIC, as evidenced by the reduced numbers of dye-coupled cells after single cell microinjection or scrape loading dye transfer. Further studies demonstrated that ER stress significantly inhibited the promoter activity of the Cx43 gene, reduced [(35)S]-methionine incorporation into Cx43 protein and accelerated degradation of Cx43. ER stress also decreased the Cx43 protein levels in several different cell types, including human umbilical vein endothelial cells, mouse-derived renin-secreting cells and human hepatoma cells. Furthermore, induction of ER stress by hypoxic chemicals thenoyltrifluoroacetone and cobalt chloride was found to be associated with a reduction in Cx43. Our findings thus reveal a close link between ER stress and GJs. ER stress may represent a novel mechanism underlying the altered GJs in a variety of pathological situations.
Huang
Tao
T
Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Wan
Yigang
Y
Zhu
Ying
Y
Fang
Xin
X
Hiramatsu
Nobuhiko
N
Hayakawa
Konihiro
K
Paton
Adrienne W
AW
Paton
James C
JC
Kitamura
Masanori
M
Yao
Jian
J
D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D018031:Connexin 43 / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology*; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D013312:Stress, Physiological / Q000187:drug effects; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology
D018031:Connexin 43; D013804:Thenoyltrifluoroacetone; D003035:Cobalt; C018021:cobaltous chloride