Connexin-based gap junction hemichannels: Gating mechanisms

Abstract

Connexins (Cxs) form hemichannels and gap junction channels. Each gap junction channel is composed of two hemichannels, also termed connexons, one from each of the coupled cells. Hemichannels are hexamers assembled in the ER, the Golgi, or a post Golgi compartment. They are transported to the cell surface in vesicles and inserted by vesicle fusion, and then dock with a hemichannel in an apposed membrane to form a cell-cell channel. It was thought that hemichannels should remain closed until docking with another hemichannel because of the leak they would provide if their permeability and conductance were like those of their corresponding cell-cell channels. Now it is clear that hemichannels formed by a number of different connexins can open in at least some cells with a finite if low probability, and that their opening can be modulated under various physiological and pathological conditions. Hemichannels open in different kinds of cells in culture with conductance and permeability properties predictable from those of the corresponding gap junction channels. Cx43 hemichannels are preferentially closed in cultured cells under resting conditions, but their open probability can be increased by the application of positive voltages and by changes in protein phosphorylation and/or redox state. In addition, increased activity can result from the recruitment of hemichannels to the plasma membrane as seen in metabolically inhibited astrocytes. Mutations of connexins that increase hemichannel open probability may explain cellular degeneration in several hereditary diseases. Taken together, the data indicate that hemichannels are gated by multiple mechanisms that independently or cooperatively affect their open probability under physiological as well as pathological conditions.

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

“…An indirect effect of S. aureus on astrocyte Cx26 expression could be envisioned to occur through an autocrine/paracrine action since both TNF-α and IL-1β are capable of activating MAPK pathways upon binding to their cognate receptors (Hanada and Yoshimura, 2002). Since Cx26 is not phosphorylated it is more likely that any indirect effects of proinflammatory stimuli would be exerted at the level of transcription/ translation (Kojima et al, 1999;Saez et al, 1998Saez et al, , 2005Traub et al, 1989). Although Temme et al (1998) have reported that IL-1 and TNF-α augment Cx26 while decreasing Cx32 mRNA expression in hepatocytes, to our knowledge, the role of proinflammatory mediators on modulating Cx26 levels in astrocytes has not yet been examined.…”

Human oligodendrocytes express Cx31.3: Function and interactions with Cx32 mutants

“…Because low calcium has been reported to activate connexin hemichannel activity (Sáez et al 2005), we examined the effect of removing calcium and magnesium from the bath solution. 15 cells expressing Cx31.3 and 6 control cells were examined in whole cell configuration with standard bath solution.…”

Lack of “Hemichannel” Activity in Insulin-Producing Cells

“…Other studies showed that leakage of cytosolic molecules and uptake of extracellular, membrane-impermeant tracers may be abolished by drugs or conditions blocking gap junction channels (Liu et al 1998;Hofer and Dermietzel 1998;Kondo et al 2000;Quist et al 2000). Finally, electrophysiology of single cells identified currents with voltage sensitivity and unitary conductances approximatively as expected for half junctional channels, made of unpaired connexons (Harris 2001;Stout et al 2004;Saez et al 2005;Spray et al 2006). Subsequently, however, the connexin hypothesis has been challenged by the evidence that proteins of the independent family of pannexins, discovered by Panchin et al (2000) and which do not form cell-to-cell channels, are prone to form the permeation pathway attributed to "hemichannels" (Bruzzone et al 2003;Bao et al 2004;Locovei et al 2006b).…”

“…Because the channels made by connexins (Cx) at gap junction domains of the cell membrane are permeated by both ions and larger molecules (Harris 2001), it was initially surmised that connexin proteins could also form single, unpaired connexons on the nonjunctional cell membrane, thereby providing the structural basis for the "hemichannels" that would account for the membrane permeation by hydrophilic molecules (Goodenough and Paul 2003;Stout et al 2004;Saez et al 2005;Spray et al 2006). Consistent with this hypothesis, biochemical, immunolabeling, and expression studies revealed that connexons may be inserted in nonjunctional regions of the cell membrane (Musil et al 1991;Paul et al 1991;De Vries et al 1992).…”

“…These findings have led to the idea that the cell membrane may contain channels permeant to molecules larger than ions, which may functionally connect the cytosol to the immediate environment of cells, at least for short 143 144 E. SCEMES ET AL. time periods (Stout et al 2004;Saez et al 2005;Spray et al 2006).…”