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 161

stresses. Intercellular communication (IC), which enables the cells in the monolayer
to react with a coordinated response, possibly helps in resilience of the endothelium
against extracellular stresses, such as exposure to inflammatory mediators, chemical
and mechanical stimuli or infection.
Purinergic signaling has been shown to be an important factor in the coordina-
tion of cellular activity and in the repertoire of defense mechanisms. For example,
adenosine is able to enhance integrity of the corneal endothelial barrier via myosin
light chain (MLC) dephosphorylation and by stimulation of fluid transport via acti-
vation of cAMP-activated Cl - channels [87, 105]. It was also shown that ATP is
able to prevent or rescue the loss of integrity of the corneal endothelial barrier by
thrombin, which is secondary to increased MLC phosphorylation [93].
10.1.3 Mechanisms of Intercellular Signaling
Intercellular signaling can take many forms. In many cell types, including endothe-
lial cells, Ca 2+ waves coordinate the activity of neighboring cells within a tissue.
Global Ca 2+ signals are produced by coordinated activity of elementary events
(influx of Ca 2+ through channels permeable to Ca 2+ , or release of Ca 2+ from intra-
cellular stores through e.g. IP3R channels) to generate an intracellular Ca 2+ wave,
which spreads throughout the cell. Ca 2+ signals then propagate into neighboring
cells, generating intercellular Ca 2+ waves. In non-excitable cells, the mechanism
of intercellular Ca 2+ communication can occur via two pathways. The first path-
way, the gap junctional intercellular communication (GJIC), occurs via the diffusion
of Ca 2+ or inositol-1,4,5-trisphosphate (IP 3 ) through gap junctions that form an
intercellular hydrophilic pathway coupling adjacent cells. The second pathway, the
paracrine intercellular communication (PIC), involves release of a diffusible extra-
cellular messenger (such as ATP) that can elicit a Ca 2+ transient in neighboring
cells via Ca 2+ influx or via Ca 2+ release from intracellular stores (Fig. 10.1A). Both
pathways can function in the same cell type, but the two pathways can also provide
communication between different cell types.
10.1.4 Mechanisms of GJIC and PIC
10.1.4.1 Cx Gap Junctions Mediate GJIC
Gap junctions are plaques of proteinaceous channels that interconnect the cytoplasm
of adjacent cells. Gap junction channels have a unitary conductance of 15-300 pS
and a diameter of approximately 1-2 nm, depending on the connexin (Cx) iso-
form present in the gap junction channel [123]. Gap junction channels are large
enough to permit a direct diffusion of ions and molecules smaller than about 1.2 kDa
between the cytoplasms of adjacent cells, and therefore are permeable to a number
of signaling molecules (e.g., Ca 2+ ,cAMP,IP 3 ) and metabolites.