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10.4.4 Physiological and Pathological Significance of PIC in
Corneal Endothelium and Other Cell Types
In humans, the corneal endothelium is a non-regenerative monolayer [52]. In a
number of situations, including mechanical injury (e.g., during intraocular surgery
such as phaco-emulsification), aging, Fuch's dystrophy, inflammation and hypoxia,
corneal endothelial cells manifest a significant change in morphology and apoptosis,
leading to loss of functional integrity of the corneal endothelial monolayer [35, 11,
14, 13]. Such changes not only affect the integrity of the corneal barrier, but can also
decrease IC, thereby hampering the coordinated response of a monolayer of cells to
extracellular stimuli. The role of the two modalities of IC (GJIC and PIC) has thus
far not been fully elucidated, but our experiments show effects on GJIC and PIC and
a possible role of IC in response to mechanical stimuli.
GJIC can be involved in intracellular homeostasis by exchange of solutes through
the gap junction channels, thereby regulating cell growth, proliferation, differenti-
ation and apoptosis [1, 28, 32]. Timely exchange of molecules via gap junctions
can protect neighboring cells from cytotoxic substances. This effect has been called
“metabolic cooperation”, “good Samaritan effect” or “kiss of life” [2, 20, 59, 69].
Exchange of molecules via gap junctions can also affect neighboring cells by
spreading factors that inhibit cell proliferation, or by transferring toxic factors or
stimuli of apoptosis to adjacent cells. Spreading of such factors has been called the
“bystander effect” or “kiss of death” [2, 20, 59, 69].
Cx-mediated GJIC is involved in the bystander effect [40, 120, 59]. In situa-
tions of injury, decrease of GJIC may attenuate the spread of toxic metabolites from
injured to healthy cells, or reduce the loss of important cellular metabolites [28]. Cxs
are known to function as tumor suppressors and numerous studies have explored
restoration of GJIC as a potential therapy against cancer [116]. Gap junctions are
down-regulated in many types of cancer, including gliomas, breast carcinoma, and
prostate cancers [67, 70]. Transfection of these cells with Cx43 leads to restoration
of gap junctions, inhibited tumor growth [130, 71].
Also PIC plays an important role in cell growth, differentiation and migration
and injury repair. PIC, via extracellular release of ATP, controls the propagation
of injury-induced Ca
2+
waves in corneal epithelial cells. This effect was due to
activation of P2Y receptors, thereby affecting cell migration and proliferation [55,
56], and activating MAPK [126]. Cx-based hemichannels also play an important
role in cell death (reviewed in [32]). Hemichannels in the plasma membrane could
affect cell death or survival by acting as (i) a pathway for loss of essential metabo-
lites or for uptake of toxic or survival enhancing substances, (ii) a transmembrane
transduction signaling pathway and (iii) as a intercellular signaling pathway (see
[31]). Recently, hemichannel-mediated PIC was suggested to regulate the prop-
agation of the cytochrome C-induced apoptotic cell death signal in concert with
gap junctions [31]. In C6 glioma cells stably transfected with Cx43, gap junctions
mediate the spread of cytochrome C-induced apoptosis in a zone next to where apop-
tosis was triggered, whereas hemichannels also promoted cell death beyond this
area [31].
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