Gap junction
Encyclopedia
A gap junction or nexus is a specialized intercellular connection between a multitude of animal cell
-types. It directly connects the cytoplasm
of two cells, which allows various molecule
s and ion
s to pass freely between cells.
One gap junction channel is composed of two connexon
s (or hemichannels) which connect across the intercellular space. Gap junctions are analogous to the plasmodesmata
that join plant cells.
s, gap junction hemichannels are primarily homo- or hetero
-hexamer
s of connexin
protein
s. Invertebrate
gap junctions comprise proteins from the hypothetical innexin
family
. However, the recently characterized pannexin
family, which was originally thought to form intercellular channels (based on similar amino acid sequence similarity to innexins), in fact functions as single-membrane channels that communicate with the extracellular environment, and have been shown to pass calcium and ATP.
At gap junctions, the intercellular space is 4 nm and unit connexons in the membrane of each cell are lined up with one another.
Gap junction channels formed from two identical hemichannels are called homotypic, while those with differing hemichannels are heterotypic. In turn, hemichannels of uniform connexin composition are called homomeric, while those with differing connexins are heteromeric. Channel composition is thought to influence the function of gap junction channels.
Generally, the gene
s coding for gap junction channels are classified in one of three groups, based on sequence similarity: A, B and C (for example, ). However, genes do not code directly for the expression of gap junction channels; genes can only produce the proteins which make up gap junction channels (connexins). An alternative naming system based on this protein's molecular weight is also popular (for example: connexin43, connexin30.3).
To date, five different functions have been ascribed to gap junction protein:
a) electrical and metabolic coupling between cells
b) Electrical and metabolic exchange through hemichannels
c) Tumor suppressor genes (Cx43, Cx32 and Cx36)
d) Adhesive function independent of conductive gap junction channel (neural migration in neocortex)
e) Role of carboxyl-terminal in signaling cytoplasmic pathways (Cx43)
: the signal to contract is passed efficiently through gap junctions, allowing the heart muscle cells to contract in tandem. Gap junctions are expressed in virtually all tissues of the body, with the exception of adult fully developed skeletal muscle and mobile cell types such as sperm
or erythrocytes. Several human genetic disorders are associated with mutations in gap junction genes. Many of those affect the skin because this tissue is heavily dependent upon gap junction communication for the regulation of differentiation and proliferation.
. The electrical synapse was discovered using electrical measurements before the gap junction structure was described. Few locations have been discovered where there is significant coupling between neuron
s in the brain. Structures in the brain that have been shown to contain electrically coupled neurons include the vestibular nucleus, the nucleus of trigeminal nerve
, the inferior olivary nucleus
, and the Ventral Tegmental Area
. There has been some observation of weak neuron to glial cell
coupling in the locus coeruleus, and in the cerebellum
between Purkinje neurons and Bergmann glial cells. It now seems that astrocyte
s are strongly coupled by gap junctions. Experimental data show strong gap junction expression in astrocytes. Moreover, mutations in the gap junction genes Cx43 and Cx56.6 cause white matter degeneration similar to that observed in Pelizaeus-Merzbacher disease
and multiple sclerosis
.
Connexin proteins expressed in neurons include:
show extensive coupling, both within populations of one cell type, and between different cell types.
. Because of the widespread occurrence of gap junctions in cell types other than nerve cells the term gap junction became more generally used than the term electrical synapse. With the purification of the intercellular gap junction plaques enriched in the channel forming protein (connexin) more systematic study and identification of the gap junction protein became possible. Refined ultrastructural studies showed the protein occurred in a complementary fashion in both cells participating in a gap junction plaque. The gap junction plaque is a relatively large area of membrane seen filled with gap junction proteins in both tissues and more gently treated gap junction preparations. With the apparent ability for one protein alone to enable intercellular communication seen in gap junctions the term gap junction tended to became synonymous with a group of assembled connexins though this was not shown in vivo. Biochemical analysis of gap junction rich isolates from various tissues demonstrated a family of connexins. Ultrastructure and biochemistry of gap junctions already referenced had indicated the connexins preferentially group in gap junction plaques or domains and connexins were the only constituent. Combining ultrastructure with immunocytochemistry showed gap junction plaques in vivo initially supported the idea that gap junctions plaques could be defined by the presence of connexins. However later studies showed gap junction plaques are home to non-connexin proteins as well making the modern usage of the term gap junction and gap junction plaque non-interchangeable.
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
-types. It directly connects the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
of two cells, which allows various molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s and ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s to pass freely between cells.
One gap junction channel is composed of two connexon
Connexon
In biology, a connexon is an assembly of six proteins called connexins that can be a part of a gap junction channel between the cytoplasm of two adjacent cells. The connexon is actually the hemichannel supplied by a cell on one side of the junction; two connexons from opposing cells normally come...
s (or hemichannels) which connect across the intercellular space. Gap junctions are analogous to the plasmodesmata
Plasmodesmata
Plasmodesmata are microscopic channels which traverse the cell walls of plant cells and some algal cells, enabling transport and communication between them. Species that have plasmodesmata include members of the Charophyceae, Charales and Coleochaetales , as well as all embryophytes, better known...
that join plant cells.
Structure
In vertebrateVertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s, gap junction hemichannels are primarily homo- or hetero
Heteromer
-Pharmacology:* Ligand-gated ion channels such as the nicotinic acetylcholine receptor and GABAA receptor are composed of five subunits arranged around a central pore that opens to allow ions to pass through. There are a large number of different subunits available, which can come together in a...
-hexamer
Hexamer
A hexamer is a thing composed out of six sub-units.In microbiology, a hexamer is one of the proteins composing the polyhedral protein shell that encloses the bacterial micro-compartments known as carboxysomes....
s of connexin
Connexin
Connexins, or gap junction proteins, are a family of structurally-related transmembrane proteins that assemble to form vertebrate gap junctions . Each gap junction is composed of two hemichannels, or connexons, which are themselves each constructed out of six connexin molecules...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s. Invertebrate
Invertebrate
An invertebrate is an animal without a backbone. The group includes 97% of all animal species – all animals except those in the chordate subphylum Vertebrata .Invertebrates form a paraphyletic group...
gap junctions comprise proteins from the hypothetical innexin
Innexin
An innexin is a member of a class of proteins which is used to create gap junctions in invertebrates. The innexin protein and its vertebrate homologue pannexin1 have 4 transmembrane spanning units and, like the vertebrate connexin gap junction protein, 6 innexin subunits together form a channel,...
family
Protein family
A protein family is a group of evolutionarily-related proteins, and is often nearly synonymous with gene family. The term protein family should not be confused with family as it is used in taxonomy....
. However, the recently characterized pannexin
Pannexin
Pannexins are a family of vertebrate proteins identified by their homology to the invertebrate innexins...
family, which was originally thought to form intercellular channels (based on similar amino acid sequence similarity to innexins), in fact functions as single-membrane channels that communicate with the extracellular environment, and have been shown to pass calcium and ATP.
At gap junctions, the intercellular space is 4 nm and unit connexons in the membrane of each cell are lined up with one another.
Gap junction channels formed from two identical hemichannels are called homotypic, while those with differing hemichannels are heterotypic. In turn, hemichannels of uniform connexin composition are called homomeric, while those with differing connexins are heteromeric. Channel composition is thought to influence the function of gap junction channels.
Generally, the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s coding for gap junction channels are classified in one of three groups, based on sequence similarity: A, B and C (for example, ). However, genes do not code directly for the expression of gap junction channels; genes can only produce the proteins which make up gap junction channels (connexins). An alternative naming system based on this protein's molecular weight is also popular (for example: connexin43, connexin30.3).
Levels of organization
- DNA to RNA to Connexin protein.
- One connexin protein has four transmembraneTransmembrane proteinA transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
domainsProtein domainA protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural... - 6 Connexins create one Connexon (hemichannel). When different connexins join together to form one connexon, it is called a heteromeric connexon
- Two hemichannels, joined together across a cell membrane comprise a Gap Junction channel.
When two identical connexons come together to form a Gap junction channel, it is called a homotypic GJ channel. When one homomeric connexon and one heteromeric connexon come together, it is called a heterotypic gap junction channel. When two heteromeric connexons join, it is also called a heteromeric Gap Junction channel. - Several gap junction channels (hundreds) assemble into a macromolecular complex called a gap junction.
Properties
- Allows for direct electrical communication between cells, although different connexin subunits can impart different single channel conductances, from about 30 pS to 500 pS.
- Allows for chemical communication between cells, through the transmission of small second messengers, such as inositol triphosphateInositol triphosphateInositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol , is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell...
(IP3) and calcium (Ca2+), although different connexin subunits can impart different selectivity for particular small molecules. - Generally allows molecules smaller than 1,000 DaltonsAtomic mass unitThe unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
to pass through, although different connexin subunits can impart different pore sizes and different charge selectivity. Large biomolecules, for example, nucleic acidNucleic acidNucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
and proteinProteinProteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, are precluded from cytoplasmic transfer between cells. - Ensures that molecules and current passing through the gap junction do not leak into the intercellular space.
To date, five different functions have been ascribed to gap junction protein:
a) electrical and metabolic coupling between cells
b) Electrical and metabolic exchange through hemichannels
c) Tumor suppressor genes (Cx43, Cx32 and Cx36)
d) Adhesive function independent of conductive gap junction channel (neural migration in neocortex)
e) Role of carboxyl-terminal in signaling cytoplasmic pathways (Cx43)
Heart
Gap junctions are particularly important in cardiac muscleCardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
: the signal to contract is passed efficiently through gap junctions, allowing the heart muscle cells to contract in tandem. Gap junctions are expressed in virtually all tissues of the body, with the exception of adult fully developed skeletal muscle and mobile cell types such as sperm
Spermatozoon
A spermatozoon is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote...
or erythrocytes. Several human genetic disorders are associated with mutations in gap junction genes. Many of those affect the skin because this tissue is heavily dependent upon gap junction communication for the regulation of differentiation and proliferation.
Neurons
A gap junction located in neurons is often referred to as an electrical synapseElectrical synapse
An electrical synapse is a mechanical and electrically conductive link between two abutting neurons that is formed at a narrow gap between the pre- and postsynaptic neurons known as a gap junction. At gap junctions, such cells approach within about 3.5 nm of each other, a much shorter...
. The electrical synapse was discovered using electrical measurements before the gap junction structure was described. Few locations have been discovered where there is significant coupling between neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s in the brain. Structures in the brain that have been shown to contain electrically coupled neurons include the vestibular nucleus, the nucleus of trigeminal nerve
Trigeminal nerve
The trigeminal nerve contains both sensory and motor fibres. It is responsible for sensation in the face and certain motor functions such as biting, chewing, and swallowing. Sensory information from the face and body is processed by parallel pathways in the central nervous system...
, the inferior olivary nucleus
Inferior olivary nucleus
The inferior olivary nucleus is the largest nucleus situated in the olivary body, part of the medulla oblongata.-Function:It is closely associated with the cerebellum, meaning that it is involved in control and coordination of movements, sensory processing and cognitive tasks likely by encoding the...
, and the Ventral Tegmental Area
Ventral tegmentum
The ventral tegmentum , better known as the ventral tegmental area , is a group of neurons located close to the midline on the floor of the midbrain...
. There has been some observation of weak neuron to glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
coupling in the locus coeruleus, and in the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
between Purkinje neurons and Bergmann glial cells. It now seems that astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s are strongly coupled by gap junctions. Experimental data show strong gap junction expression in astrocytes. Moreover, mutations in the gap junction genes Cx43 and Cx56.6 cause white matter degeneration similar to that observed in Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Pelizaeus–Merzbacher disease is a rare central nervous system disorder in which coordination, motor abilities, and intellectual function are delayed to variable extents.-Classification:...
and multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
.
Connexin proteins expressed in neurons include:
- mCX26
- mCX43
- mCX36
- mCX56.6
- mCX57
- mCX45
Retina
Neurons within the retinaRetina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
show extensive coupling, both within populations of one cell type, and between different cell types.
Discovery
Gap junctions were so named because of the "gap" shown to be present at these special junctions between two cells. A similar regular gap was not demonstrated in other intercellular junctions described at the time. Well before this demonstration of the "gap" in gap junctions they were seen at the junction of neighboring nerve cells and proven to be electrically rectifying and so referred to as an electrical synapseElectrical synapse
An electrical synapse is a mechanical and electrically conductive link between two abutting neurons that is formed at a narrow gap between the pre- and postsynaptic neurons known as a gap junction. At gap junctions, such cells approach within about 3.5 nm of each other, a much shorter...
. Because of the widespread occurrence of gap junctions in cell types other than nerve cells the term gap junction became more generally used than the term electrical synapse. With the purification of the intercellular gap junction plaques enriched in the channel forming protein (connexin) more systematic study and identification of the gap junction protein became possible. Refined ultrastructural studies showed the protein occurred in a complementary fashion in both cells participating in a gap junction plaque. The gap junction plaque is a relatively large area of membrane seen filled with gap junction proteins in both tissues and more gently treated gap junction preparations. With the apparent ability for one protein alone to enable intercellular communication seen in gap junctions the term gap junction tended to became synonymous with a group of assembled connexins though this was not shown in vivo. Biochemical analysis of gap junction rich isolates from various tissues demonstrated a family of connexins. Ultrastructure and biochemistry of gap junctions already referenced had indicated the connexins preferentially group in gap junction plaques or domains and connexins were the only constituent. Combining ultrastructure with immunocytochemistry showed gap junction plaques in vivo initially supported the idea that gap junctions plaques could be defined by the presence of connexins. However later studies showed gap junction plaques are home to non-connexin proteins as well making the modern usage of the term gap junction and gap junction plaque non-interchangeable.
See also
- Electrical synapseElectrical synapseAn electrical synapse is a mechanical and electrically conductive link between two abutting neurons that is formed at a narrow gap between the pre- and postsynaptic neurons known as a gap junction. At gap junctions, such cells approach within about 3.5 nm of each other, a much shorter...
- Ion channelIon channelIon channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
- Junctional complex
- Intercalated discIntercalated discWhen observing cardiac tissue through a microscope, intercalated discs are an identifying feature of cardiac muscle. Cardiac muscle consists of single heart muscle cells which have to be connected by intercalated discs to work as a functional organ. By contrast, skeletal muscle consists of...
- Cardiac muscleCardiac muscleCardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
- Tight junctionTight junctionTight junctions, or zonula occludens, are the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. It is a type of junctional complex present only in vertebrates...
- Desmosomes