Biology Reference
In-Depth Information
Gap junction channels are formed by the docking of two hemichannels (also
called connexons) of adjacent cells. Each connexon comprises six integral trans-
membrane proteins called connexins (Cxs), which are radially arranged around a
central pore (Fig. 10.1B).
Cxs belong to a superfamily that also includes innexins, which form gap junc-
tions in invertebrates, and pannexins (Panx), which are found in many species,
including mammals (for review see [129]). Cx isoforms are members of the highly
conserved multigenic family of transmembrane proteins consisting of about 20
members, and are named on the basis of their molecular weight (between 26 and
60 kDa) [25]. Corneal endothelial cells express several Cx subtypes, including
Cx26, Cx31, Cx32, Cx36, Cx43, Cx45, and Cx50. As in many other cell types,
the most abundant Cx subtype is Cx43.
Cxs are folded in the membrane in the approximate shape of an “M”. They con-
tain four membrane-spanning domains (M1 to M4), two extracellular loops (named
EL1 and EL2), which are involved in the docking of two connexons and which
connect M1 with M2 and M3 with M4, respectively, one cytoplasmic loop (CL;
connecting M2 and M3), and the cytoplasmic N- and C-terminal domains. The M3
membrane-spanning domain of each Cx contains a high proportion of hydrophilic
amino acids, and is the major pore-lining helix of the gap junction channel. M1 con-
tributes to the lining of the pore, while M2 appears to contribute to the mouth of the
pore. The sequences of the N- and C- terminal domains in the cytoplasm are very
diverse between different Cx subtypes. Both the highly variable cytoplasmic loop
and C-terminus may be involved in the cellular regulation of gap junction forma-
tion and channel permeability. The activity of the channel is closely regulated by
phosphorylation or via protein-protein interactions [46, 90, 42, 60, 92, 47].
10.1.4.2 Hemichannel-Mediated ATP Release can Produce PIC
PIC takes place via the release of signaling molecules in the extracellular space that
induce a response in neighbouring target cells expressing receptors for the signaling
molecules. The released messengers can act on the receptors on target cells in close
proximity (PIC) or on distant target cells (endocrine signaling), and they can also
eventually act on the releasing cell (autocrine effect). While some messengers, such
as arachidonic acid and nitric oxide (NO), are lipophilic, penetrating the membrane
and acting on intracellular receptors, many paracrine messengers are hydrophilic
and bind as ligands to receptor proteins that are present in the plasma membrane.
A major form of PIC evoked by hydrophilic messengers is mediated by
nucleotides (for review see [19]). Extracellular nucleotides, such as ADP and ATP,
as well as adenosine, are important signaling molecules involved in paracrine
intercellular communication.
ATP is known to be released from many cell types, and several mechanisms can
be involved in the release of ATP and other nucleotides, depending on the conditions
and cell types. The contribution of the different pathways to ATP release under
various conditions in different cell types is still very controversial.
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