Gap junction and hemichannel-independent actions of connexins on cell and tissue functions--an update

Abstract

Connexins, a family of transmembrane proteins, are components of both gap junction channels and hemichannels, which mediate the exchange of ions and small molecules between adjacent cells, and between the inside and outside of the cell, respectively. Substantial advancements have been made in the comprehension of the role of gap junctions and hemichannels in coordinating cellular events. In recent years, a plethora of studies demonstrate a role of connexin proteins in the regulation of tissue homeostasis that occurs independently of their channel activities. This is shown in the context of cell growth, adhesion, migration, apoptosis, and signaling. The major mechanisms of these channel-independent activities still remain to be discovered. In this review, we provide an updated overview on the current knowledge of gap junction- and hemichannel-independent functions of connexins, in particular, their effects on tumorigenesis, neurogenesis and disease development.

Keywords: Connexin; Gap junction; Hemichannel; Independent function.

Fig. 1

Non-GJIC tumor promoting and tumor suppressing effects of connexins. The non-GJIC effects of connexins on tumor behavior can be separated into tumor promoter and tumor suppresser categories. These effects may further be subcategorized into influences on the tumor growth, migration, cell cycle, apoptosis, and EMT.

Fig. 2

Interaction between the connexin 43 C-terminal tail and signaling factors. The C-terminal tail of Cx43 interacts with many signaling factors and regulators of cancer behavior. Phosphorylation of tyrosine 247 and 265 of the C-terminal tail inhibits c-Src activity and decreases proliferation of glioma cells [35,36] (A). Phosphorylation of serines 255, 262, 279, and 282 of the C-terminal tail by MAPK increases proliferation of vascular smooth muscle cells [52] (B). Phosphorylation of serine 262 of the CT by PKC inhibits DNA synthesis in HEK293 cells [41] and leads to cardiac ischemic injury resistance [48] (C). Interaction of the CT with Cav-1 reduces human keratinocyte skin tumor transformation and invasion [34] (D). Interaction of the CT amino acids 257–382 with CCN3 decreases growth of 293T human embryonic kidney epithelial cells [38] (E).