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  • Review Article
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Beyond the gap: functions of unpaired connexon channels

Nature Reviews Molecular Cell Biology volume 4, pages 285–295 (2003)Cite this article

Key Points

  • Gap junctions are aggregates of intercellular channels that join adjacent cells. Intercellular channels are composed of a pair of connexons, each of which is a hexamer of connexin proteins. As precursors to the intercellular channels, connexons can be found in the plasma membranes of cells. In some cellular systems, however, connexons might function independently of gap junctions.

  • Although there are data implicating gap-junctional intercellular channels in the cell–cell transmission of Ca2+ waves, it is also clear that these waves can spread by paracrine signalling owing to the extracellular release of ATP that binds to purinergic receptors. Evidence is accumulating that the connexon might provide a regulated channel that is responsible for the ATP release.

  • The bisphosphonate alendronate has been shown to have an anti-apoptotic effect on bone cells. Recent data indicate that connexons might be the receptor for alendronate, transducing a survival signal through the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway.

  • A long-standing puzzle has been the interaction of retinal horizontal cells with cones as part of centre-surround antagonism. The interaction between these cells might involve connexons. The voltage-induced opening of connexons in the horizontal-cell membrane might function to create a negative extracellular potential in the invaginating synapses of the cone pedicles, opening Ca2+ channels and stimulating glutamate release.

Abstract

Gap junctions consist of intercellular channels that connect the cytoplasm of adjacent cells directly and allow the exchange of small molecules. These channels are unique in that they span two plasma membranes — the more orthodox ion or ligand-gated channels span only one. Each cell contributes half of the intercellular channel, and each half is known as a connexon or hemichannel. Recent studies indicate that connexons are also active in single plasma membranes and that they might be essential in intercellular signalling beyond their incorporation into gap junctions.

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Figure 1: Connexins, connexons, intercellular channels and gap junctions.
Figure 2: Connexons and nucleotide transport.
Figure 3: Connexon-mediated apoptosis.
Figure 4: A diagram of a cone pedicle with an invaginating synapse.

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Acknowledgements

Work in the authors' laboratories is supported by grants from the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Boston, 02115, MA, USA

    Daniel A. Goodenough

  2. Department of Neurobiology, Harvard Medical School, Boston, 02115, MA, USA

    David L. Paul

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  1. Daniel A. Goodenough
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Correspondence to Daniel A. Goodenough.

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DATABASES

OMIM

X-linked Charcot–Marie–Tooth disease

Swiss-Prot

Bcl-2

CD38

Cx26

Cx32

Cx35

Cx38

Cx43

Cx45

Cx46

Cx50

Cx56

Src

FURTHER INFORMATION

Daniel A. Goodenough's laboratory

Glossary

METAZOA

A subkingdom of animals that includes all multicellular organisms with differentiated tissues.

HEMICHORDATES

A phylum of bilaterally symmetric marine animals with gill slits to the pharynx.

ACTION POTENTIAL

A self-propagating opening of voltage-gated channels along the length of a cell.

GRANULOSA CELL

A cell type found in mammalian ovarian follicles that surrounds the developing oocyte.

NON-SYNDROMIC DEAFNESS

Deafness that is unaccompanied by other clinical manifestations.

SURFACE-LABELLING

The chemical modification of cell-surface molecules using reagents that are membrane impermeant.

SUCROSE GRADIENT FRACTIONATION

The biochemical separation of subcellular components on the basis of their buoyant density.

CROSSLINKING

The use of bifunctional reactive compounds to covalently couple molecules that are in close proximity.

TELEOST HORIZONTAL CELL

A cell type that is found in fish retinas.

SCHWANN CELL

A glial cell in the peripheral nervous system that is responsible for the myelination of axons.

PARANODAL MEMBRANE

A plasma membrane that surrounds non-compact areas of Schwann cells that are found immediately adjacent to nodes of Ranvier.

INCISURE OF SCHMIDT-LANTERMAN

A spiralling region of non-compact myelin that joins the periaxonal with the perinuclear cytoplasm in myelinating glia.

NOVIKOFF HEPATOMA CELLS

A cell line derived from a liver tumour that is used in the study of gap-junctional intercellular communication.

ASTROCYTES

One of several classes of glia (non-neuronal support cells) that are found in the central nervous system.

VENTRICULAR MYOCYTE

A cell that is found in the ventricles of the heart.

N2A NEUROBLASTOMA CELLS

A cell line derived from a brain tumour that has very low endogenous connexin expression, and is useful for studying the introduction of exogenous connexins.

OLEAMIDE

(9(Z)-octadecenamide). A sleep-inducing lipid that was first isolated from the cerebrospinal fluid of sleep-deprived cats. It rapidly and reversibly closes gap-junctional channels.

18 α-GLYCYRRHETINIC ACID

A lipophilic saponin isolated from liquorice roots that blocks gap-junction channels and connexons.

C6 GLIOMA CELLS

A cell line derived from a glioma that is used to study intercellular communication and Ca2+ waves.

OSTEOCYTE

A differentiated bone cell that is trapped in lamellar bone. Osteocytes are interconnected by gap junctions by processes that extend through long canaliculi.

P2 PURINERGIC RECEPTOR

A cell-surface ATP receptor.

LIPOSOME

A unilamellar vesicle.

OSTEOBLAST

A bone cell that synthesizes and secretes osteoid, which is the extracellular matrix of bone. Osteoblasts differentiate into osteocytes.

OSTEOGENESIS

The process of bone formation.

OSTEOCLAST

A mesenchymal cell that can differentiate into a bone-degrading cell.

PEDICLE

The ending of a cone cell that interacts with other neurons in the retina.

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Goodenough, D., Paul, D. Beyond the gap: functions of unpaired connexon channels. Nat Rev Mol Cell Biol 4, 285–295 (2003). https://doi.org/10.1038/nrm1072

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