ATP Release Via Connexin Hemichannels Controls Intercellular Propagation of Ca Waves in Corneal Endothelial Cells - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 183

In addition, Cx43 hemichannels are regulated by the redox potential and oxida-
tive stress. On the one hand, reducing the intracellular redox potential, either
by chemical reducing agents like DTT or by intracellular physiological reduc-
ing molecules like GSH enhanced Cx43-hemichannel activity [85]. This effect of
reducing agents on the opening of Cx43 hemichannels is likely mediated by reduc-
tion of intracellular cysteines that are located in the C-terminal tail of Cx43. On
the other hand, opening of Cx43 hemichannels is induced by metabolic inhibition
or ischemic conditions, which leads to intracellular accumulation of NO, and S-
nitrosylation of the three intracellular cysteines located in the C-terminal tail of
Cx43 hemichannels [84]. The exact mechanism by which the redox potential and
oxidative stress regulates hemichannel opening still remains to be elucidated. It
is not definitely clear how reducing agents inhibit the increase in hemichannel
permeability caused by oxidative stress during metabolic inhibition, but enhance
hemichannel opening under normoxic conditions. This may suggest that the same
cysteine residues are substrates of different redox reactions, including formation
and reduction of disulfide bonds, cysteine S-nitrosylation, and/or glutathionation
[4]. Alternatively, depending on the Cx43-phosphorylation states, or on the presence
of Cx43-interaction partners, the same modifications may lead to different confor-
mational changes or modulation of different cysteine residues. Therefore, it will be
essential to identify the physiological function for each of the three cysteine residues
in the intracellular tail of Cx43 by site-directed mutagenesis approaches.
Not only Cx channels play a role in the propagation of factors that inhibit cell
proliferation, but also Panx channels, which mainly form hemichannels [9, 10], con-
trol inflammatory responses and cell death. Panx1 levels are elevated upon exposure
to diverse pro-inflammatory stimuli (e.g., TNF- , lipopolysaccha-

ride, cold and systemic inflammation) [104]. Panx1 hemichannels represent the
non-selective pore that opens upon P2X7 activation, thereby facilitating the entry
of pro-inflammatory molecules into the cytosol required for activation of cryopyrin-
dependent inflammosome and caspase-1 cleavage [98, 122, 119, 76, 54, 77]. In
addition, it has been shown that a component of IL-1 cytokine release through
ATP-dependent activation of P2X7 is dependent on Panx1 [75]. Furthermore, the
P2X7/Panx1-protein complex controls the expression of several proteins and par-
ticipates in wound healing [66]. The link of Panx1 opening with ATP-induced
stimulation of P2X7 also contributed to ATP-induced cell death [76]. In addition,
in acute glaucoma conditions, Panx hemichannels mediate increased ATP release
during retinal pressure elevation, leading to the death of ganglion cells [83].
Furthermore, Panx1 activation causes neuronal excitotoxicity during stroke, lead-
ing to swelling, Ca 2+ dysregulation and ischemic neuronal death in pyramidal
neurons, which express endogenous Panx1 [114]. Opening of Panx1 hemichan-
nels at postsynaptic sites [131], is triggered by NMDAR activation, resulting in
rhythmic epileptiform-like bursting, which correlates to the bursting observed in
epilepsy patients [113]. Finally, the opening of large numbers of hemichannels fol-
lowing ischemia or inflammatory injury may also be involved in pathophysiological
cascades leading to cell depolarization, collapse of ionic gradients, loss of small
metabolites and elevation of intracellular Ca 2+ [104].

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