In
biology
Biology is the scientific study of life and living organisms. It is a broad natural science that encompasses a wide range of fields and unifying principles that explain the structure, function, growth, History of life, origin, evolution, and ...
, a connexon, also known as a connexin hemichannel, is an assembly of six proteins called
connexin
Connexins (Cx)TC# 1.A.24, or gap junction proteins, are structurally related transmembrane proteins that assemble to form vertebrate gap junctions. An entirely different family of proteins, the innexins, forms gap junctions in invertebrates. Eac ...
s that form the pore for a
gap junction
Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such small molecules, substrates, and metabolites.
Gap junctions were first described as ''close appositions'' alongside tight ...
between the
cytoplasm
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
of two adjacent
cells. This channel allows for bidirectional flow of ions and signaling molecules.
The connexon is the
hemichannel supplied by a cell on one side of the junction; two connexons from opposing cells normally come together to form the complete intercellular gap junction channel. In some cells, the hemichannel itself is active as a conduit between the cytoplasm and the
extracellular space, allowing the transference of ions and small molecules lower than 1-2 KDa. Little is known about this function of connexons besides the new evidence suggesting their key role in
intracellular signaling.
In still other cells connexons have been shown to occur in mitochondrial membranes and appear to play a role in heart
ischaemia.
Connexons made of the same type of connexins are considered
homomeric, while connexons made of differing types of connexins are
heteromeric.
Structure
Assembly
The assembly of connexins destined for gap junction plaques begins with synthesis of connexins within the cell and ends with the formation of gap junction channel plaques on the cell membrane. The connexin subunit proteins that make up connexons are synthesized on the membranes of the cell's
endoplasmic reticulum
The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
. These subunits are then
oligomer
In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
ized, or combined with other smaller parts, into connexons in the
golgi apparatus
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...
.
The connexons are then delivered to their proper location on the plasma membrane. Connexons then dock with compatible connexons from the neighboring cell to form gap junction channel plaques.
A large part of this process is mediated by
phosphorylation
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writ ...
of different enzymes and proteins, allowing and preventing interaction between certain proteins.
The connexons forming channels to the cell exterior or in mitochondria will require a somewhat altered path of assembly.
General
Connexons contribute to the formation of gap junctions, and are an essential component of the electric synapses in neural pathways.
In a single gap junction, connexons will assemble around an aqueous porous membrane, forming a hemi-channel that is composed of connexins. Connexins are the smaller protein molecules that make up connexons and play a crucial part to the formation of gap junctions. Structurally, connexins are made up of 4
alpha helical transmembrane domains connected by two extracellular loops and one cytoplasmic loop, while both
N and
C terminals reside intracellularly. Connexin types can be further differentiated by using their predicted
molecular weight
A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...
(ex: Connexin 43 is Cx 43 due to its molecular weight of 43 kDa). Connexons will form the gap junction by docking a hemi-channel to another hemi-channel in an adjacent cell membrane.
During this phase, the formation of intercellular channels spanning both of the plasma membranes occurs. Subsequently, this process leads to a better understanding of how electric synapses are facilitated between neurons.
Early research identified connexons through their presence in gap junctions. Since then, connexons have been increasingly detected forming channels in single membranes considerably broadening their functionality in cells and tissues.
Degradation
Connexon structure is degraded by its removal from the plasma membrane. Connexons will be internalized by the cell itself as a double membrane channel structure (due to the docking of hemi-channels).
This is called internalization or
endocytosis
Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...
. Research suggests that gap junctions in general may be internalized using more than one method, but the best known and most studied would be that of
clathrin-mediated endocytosis.
In simple terms this process consists of a
ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
binding to a receptor signaling for a certain part of the membrane to be coated in
clathrin.
This part of the membrane then buds into the cell forming a
vesicle. Now present in the cell membrane, connexons will be degraded by
lysosomal pathways.
Lysosomes are able to break down the proteins of the connexon because they contain specific
enzymes
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...
that are made specifically for this process. It is thought that
ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...
signals degradation within the cell.
Cellular functions
Properties
The properties of individual connexin proteins determine the overall properties of the whole connexon channel. The
permeability and selectivity of the channels is determined by its width as well as the molecular selectivity of connexins such as charge selectivity.
Research shows connexons are particularly permeable to
soluble
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solubi ...
second messengers
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first m ...
,
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...
,
nucleotides
Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
, ions and glucose.
Channels are also voltage sensitive. The connexon channels have voltage-dependent gates that open or close depending on the difference in
voltage
Voltage, also known as (electrical) potential difference, electric pressure, or electric tension, is the difference in electric potential between two points. In a Electrostatics, static electric field, it corresponds to the Work (electrical), ...
between the interiors of the two cells.
Gates can also show voltage sensitivity depending on the difference in voltage from the interior and exterior of the cell (i.e.
membrane potential
Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. It equals the interior potential minus the exterior potential. This is th ...
).
Modulation
Communication between gap-junctions can be modulated/regulated in many ways. The main types of modulation are:
*Chemical – one common type of chemical modulation is through the interaction of Ca
2+ and certain domains of connexins. It is not completely understood, however, it is suggested that this interaction causes Ca
2+ to block the
pore of the channel. Another form of chemical modulation is through the response of the channel to acidification (decrease of
intracellular pH). It has been found that intracellular acidification causes a change in the
C-terminal domain of connexins which then reduces the channel activity.
*Protein Phosphorylation – protein
phosphorylation
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writ ...
regulates the communication between channels in multiple ways by controlling: connexin trafficking from the Golgi Apparatus, accumulation of connexons to certain areas, and degradation of unnecessary channels. The process of these actions is very complex but involvement of protein phosphorylation is known.
*Humoral – humoral modulation of gap junction communication is done through many biomolecules such as
neurotransmitters
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.
Neurotransmitters are rele ...
,
growth factors
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
, and various
bioactive compounds. Neurotransmitters such as
epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
and
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
work in neuronal gap-junctions causing propagation of
action potentials
An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific cell rapidly rises and falls. ...
down neurons. These types of gap-junctions with this type of modulation are often found in neurons in cardiac tissue and vertebrate retina.
Overall functions
Connexons play an imperative role in behavior and neurophysiology. Many of the details surrounding their pathological functions remain unknown as research has only begun recently. In the central nervous system (CNS), connexons play a major role in conditions such as
epilepsy
Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
,
ischemia
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
,
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
, and
neurodegeneration
A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their cell death, death. Neurodegenerative diseases include amyotrophic lateral sc ...
.
The molecular mechanism as to how connexons play a role in the conditions listed above has yet to be fully understood and is under further research. Along with their key role in the CNS, connexons are crucial in the functioning of cardiac tissues. The direct connection allows for quick and synchronized firing of neurons in the heart which explains the ability for the heart to beat quickly and change its rate in response to certain stimuli.
Connexons also play an essential role in cell development. Specifically, their role in
neurogenesis
Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...
dealing with brain development as well as brain repair during certain diseases/pathologies and also assisting in both cell division as well as cell proliferation. The mechanism by which connexons aid in these processes is still being researched however, it is currently understood that this mechanism involves
purinergic signaling (form of extracellular signaling mediated by purine nucleotides and nucleosides such as adenosine and ATP) and permeability to ATP.
Other important roles of connexons are glucose sensing and
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
. Connexons cause changes in extracellular glucose concentrations affecting feeding/satiety behavior, sleep-wake cycles, and energy use.
Further studies indicate that there is an increase in glucose uptake mediated by connexons (whose mechanism is still not fully understood) and under times of high stress and inflammation.
Recent research also indicates that connexons may affect
synaptic plasticity
In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...
, learning, memory, vision, and sensorimotor gating.
Related diseases
Some of the diseases associated with connexons are
cardiovascular disease
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
and
diabetes
Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
, which is the inability of the body to produce insulin for glucose uptake by cells and degradation in the smaller units of connexons, called connexins, possibly leading to the onset of heart disease. Cardiovascular disease and diabetes, type I and II, affects similar locations within cells of the heart and pancreas. This location is the gap junction, where connexons facilitate rapid cell-to-cell interactions via electrical transmissions. Gap junctions are often present at nerve endings such as in cardiac muscle and are important in maintaining
homeostasis
In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
in the liver and proper function of the kidneys. The gap junction itself is a structure that is a specialized transmembrane protein formed by a connexon hemichannel.
Cardiovascular disease and possibly type I and II diabetes, are each associated with a major protein connexin that makes up the gap junction.
In cardiovascular disease, Cx43 (connexin 43), a subunit of a connexon, is a general protein of the gap junction stimulating cardio
myocyte
A muscle cell, also known as a myocyte, is a mature contractile Cell (biology), cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal muscle, skeletal, smooth muscle, smooth, and Cardiac muscle, cardiac ...
muscle cells of intercalated discs facilitating synchronized beating of the heart. In the occurrence of cardiovascular disease the Cx43 subunit begins to show signs of oxidative stress, the ability of the heart to counteract the buildup of harmful toxins due to age or diet leading to reduced vascular functions.
Additionally, reduced Cx43 expression in vascular tissue, which plays a part in ventricular remolding and healing of wounds after a
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
, are present in structural heart disease.
However, the mechanisms of Cx43 in the heart are still poorly understood.
Overall, these changes in Cx43 expression and oxidant stress can lead to abnormalities in the coordinated beating of the heart, predisposing it to cardiac
arrhythmias
Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beats ...
.
Connexons are also associated with both
Type I and
Type II diabetes. Cx36 (connexin 36) subunit mediates
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
excretion and glucose-induced insulin release from gap junctions of the liver and pancreas.
Homeostasis in the liver and pancreatic organs are supported by an intricate system of cellular interactions called endocrine signaling. The secretion of hormones into the blood stream to target distant organs. However, endocrine signaling in the pancreas and liver operates along short distances in the cellular membrane by way of signaling pathways, ion channels,
G-protein coupled receptors,
tyrosine-kinase receptors, and cell-to-cell contact.
The gap junctions in these tissues supported by endocrine signaling arbitrate intracellular signals between cells and larger organ systems by connecting adjacent cells to each other in a tight fit. The Tight fit of the gap junction is such that cells in the tissue can communicate more efficiently and maintain homeostasis. Thus the purpose of the gap junction is to regulate the passage of ions, nutrients, metabolites, second messengers, and small biological molecules.
In diabetes the subsequent loss or degradation of Cx36 substantially inhibits insulin production in the pancreas and glucose in the liver which is vital for the production of energy for the entire body. A deficiency of Cx36 adversely affects the ability of the gap junction to operate within these tissues leading a reduction in function and possible disease. Similar symptoms associated with the loss or degradation of the gap junction have been observed in type II diabetes, however, the function of Cx36 in Type 1 and type II diabetes in humans is still unknown. Additionally, the Cx36 connexin is coded for by GJD2 gene, which has a predisposition on the gene locus for type II diabetes, and diabetic syndrome.
References
Further reading
*
{{Authority control
Cytoplasm
Membrane biology