Connexon

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Connexon
Connexon and connexin structure.svg
Connexon and connexin structure
Details
Identifiers
Latin connexona
TH H1.00.01.1.02025
Anatomical terminology

In biology, a connexon, also known as a connexin hemichannel, is an assembly of six proteins called connexins that form the pore for a gap junction between the cytoplasm of two adjacent cells. This channel allows for bidirectional flow of ions and signaling molecules. [1] 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. [2] In still other cells connexons have been shown to occur in mitochondrial membranes and appear to play a role in heart ischaemia. [3]

Contents

Connexons made of the same type of connexins are considered homomeric, while connexons made of differing types of connexins are heteromeric. [4]

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. These subunits are then oligomerized, or combined with other smaller parts, into connexons in the golgi apparatus. [5] The connexons are then delivered to their proper location on the plasma membrane. [6] Connexons then dock with compatible connexons from the neighboring cell to form gap junction channel plaques. [5] A large part of this process is mediated by phosphorylation of different enzymes and proteins, allowing and preventing interaction between certain proteins. [5] 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. [5] 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 (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. [2] 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. [2] 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. [7]

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). [5] This is called internalization or endocytosis. 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. [5] In simple terms this process consists of a ligand binding to a receptor signaling for a certain part of the membrane to be coated in clathrin. [5] 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. [5] Lysosomes are able to break down the proteins of the connexon because they contain specific enzymes that are made specifically for this process. It is thought that ubiquitination signals degradation within the cell. [5]

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. [2] Research shows connexons are particularly permeable to soluble second messengers, amino acids, nucleotides, ions and glucose. [2] Channels are also voltage sensitive. The connexon channels have voltage-dependent gates that open or close depending on the difference in voltage between the interiors of the two cells. [2] Gates can also show voltage sensitivity depending on the difference in voltage from the interior and exterior of the cell (i.e. membrane potential). [2]

Modulation

Communication between gap-junctions can be modulated/regulated in many ways. The main types of modulation are:

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, ischemia, inflammation, and neurodegeneration. [1] 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. [2] Connexons also play an essential role in cell development. Specifically, their role in neurogenesis 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. [1] Other important roles of connexons are glucose sensing and signal transduction. Connexons cause changes in extracellular glucose concentrations affecting feeding/satiety behavior, sleep-wake cycles, and energy use. [1] 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. [1] Recent research also indicates that connexons may affect synaptic plasticity, learning, memory, vision, and sensorimotor gating.

Some of the diseases associated with connexons are cardiovascular disease and diabetes, 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 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. [8] 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 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. [8] Additionally, reduced Cx43 expression in vascular tissue, which plays a part in ventricular remolding and healing of wounds after a myocardial infarction, are present in structural heart disease. [9] However, the mechanisms of Cx43 in the heart are still poorly understood. [9] 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. [8]

Connexons are also associated with both Type I and Type II diabetes. Cx36 (connexin 36) subunit mediates insulin excretion and glucose-induced insulin release from gap junctions of the liver and pancreas. [4] 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. [4] 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. [4] 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. [4]

Related Research Articles

Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, and to reduce chest pain caused by angina pectoris.

<span class="mw-page-title-main">Gap junction</span> Cell-cell junction composed of innexins or connexins,

Gap junctions are one of three broad categories of intercellular connections that form between a multitude of animal cell types. First photographed around 1952, it wasn't until 1969 that gap junctions were referred to as gap junctions. Named after the 2-4 nm gap they bridged between cell membranes, they had been characterised in more detail by 1967.

<span class="mw-page-title-main">Electrical synapse</span> Type of connection between neurons

An electrical synapse is a mechanical and electrically conductive synapse, a functional junction between two neighboring neurons. The synapse 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 3.8 nm of each other, a much shorter distance than the 20- to 40-nanometer distance that separates cells at a chemical synapse. In many animals, electrical synapse-based systems co-exist with chemical synapses.

<span class="mw-page-title-main">Cell adhesion</span> Process of cell attachment

Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.

<span class="mw-page-title-main">Connexin</span> Group of proteins which form the intermembrane channels of gap junctions

Connexins (Cx), or gap junction proteins, are structurally related transmembrane proteins that assemble to form vertebrate gap junctions. An entirely different family of proteins, the innexins, form gap junctions in invertebrates. Each gap junction is composed of two hemichannels, or connexons, which consist of homo- or heterohexameric arrays of connexins, and the connexon in one plasma membrane docks end-to-end with a connexon in the membrane of a closely opposed cell. The hemichannel is made of six connexin subunits, each of which consist of four transmembrane segments. Gap junctions are essential for many physiological processes, such as the coordinated depolarization of cardiac muscle, proper embryonic development, and the conducted response in microvasculature. Connexins also have non-channel dependant functions relating to cytoskeleton and cell migration. For these reasons, mutations in connexin-encoding genes can lead to functional and developmental abnormalities.

<span class="mw-page-title-main">Cell junction</span> Multiprotein complex that forms a point of contact or adhesion in animal cells

Cell junctions or junctional complexes are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals. They also maintain the paracellular barrier of epithelia and control paracellular transport. Cell junctions are especially abundant in epithelial tissues. Combined with cell adhesion molecules and extracellular matrix, cell junctions help hold animal cells together.

An ATP-sensitive potassium channel is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) subunits, along with additional components. KATP channels are widely distributed in plasma membranes; however some may also be found on subcellular membranes. These latter classes of KATP channels can be classified as being either sarcolemmal ("sarcKATP"), mitochondrial ("mitoKATP"), or nuclear ("nucKATP").

<span class="mw-page-title-main">Pannexin</span>

Pannexins are a family of vertebrate proteins identified by their homology to the invertebrate innexins. While innexins are responsible for forming gap junctions in invertebrates, the pannexins have been shown to predominantly exist as large transmembrane channels connecting the intracellular and extracellular space, allowing the passage of ions and small molecules between these compartments.

Innexins are transmembrane proteins that form gap junctions in invertebrates. Gap junctions are composed of membrane proteins that form a channel permeable to ions and small molecules connecting the cytoplasm of adjacent cells. Although gap junctions provide similar functions in all multicellular organisms, it was not known what proteins invertebrates used for this purpose until the late 1990s. While the connexin family of gap junction proteins was well-characterized in vertebrates, no homologues were found in non-chordates.

T-type calcium channels are low voltage activated calcium channels that become inactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac muscle cell and smooth muscle cells voltage-gated calcium channel activation initiates contraction directly by allowing the cytosolic concentration to increase. Not only are T-type calcium channels known to be present within cardiac and smooth muscle, but they also are present in many neuronal cells within the central nervous system. Different experimental studies within the 1970s allowed for the distinction of T-type calcium channels from the already well-known L-type calcium channels. The new T-type channels were much different from the L-type calcium channels due to their ability to be activated by more negative membrane potentials, had small single channel conductance, and also were unresponsive to calcium antagonist drugs that were present. These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system.

Membrane channels are a family of biological membrane proteins which allow the passive movement of ions, water (aquaporins) or other solutes to passively pass through the membrane down their electrochemical gradient. They are studied using a range of channelomics experimental and mathematical techniques. Insights have suggested endocannabinoids (eCBs) as molecules that can regulate the opening of these channels during diverse conditions.

<span class="mw-page-title-main">GJA1</span> Protein-coding gene in humans

Gap junction alpha-1 protein (GJA1), also known as connexin 43 (Cx43), is a protein that in humans is encoded by the GJA1 gene on chromosome 6. As a connexin, GJA1 is a component of gap junctions, which allow for gap junction intercellular communication (GJIC) between cells to regulate cell death, proliferation, and differentiation. As a result of its function, GJA1 is implicated in many biological processes, including muscle contraction, embryonic development, inflammation, and spermatogenesis, as well as diseases, including oculodentodigital dysplasia (ODDD), heart malformations, and cancers.

<span class="mw-page-title-main">GJB1</span> Protein-coding gene in humans

Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), is a transmembrane protein that in humans is encoded by the GJB1 gene. Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulates and controls the transfer of communication signals across cell membranes, primarily in the liver and peripheral nervous system. However, the protein is expressed in multiple organs, including in oligodendrocytes in the central nervous system.

<span class="mw-page-title-main">GJB6</span> Protein-coding gene in the species Homo sapiens

Gap junction beta-6 protein (GJB6), also known as connexin 30 (Cx30) — is a protein that in humans is encoded by the GJB6 gene. Connexin 30 (Cx30) is one of several gap junction proteins expressed in the inner ear. Mutations in gap junction genes have been found to lead to both syndromic and nonsyndromic deafness. Mutations in this gene are associated with Clouston syndrome.

<span class="mw-page-title-main">KCNE4</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily E member 4, originally named MinK-related peptide 3 or MiRP3 when it was discovered, is a protein that in humans is encoded by the KCNE4 gene.

Cell–cell interaction refers to the direct interactions between cell surfaces that play a crucial role in the development and function of multicellular organisms. These interactions allow cells to communicate with each other in response to changes in their microenvironment. This ability to send and receive signals is essential for the survival of the cell. Interactions between cells can be stable such as those made through cell junctions. These junctions are involved in the communication and organization of cells within a particular tissue. Others are transient or temporary such as those between cells of the immune system or the interactions involved in tissue inflammation. These types of intercellular interactions are distinguished from other types such as those between cells and the extracellular matrix. The loss of communication between cells can result in uncontrollable cell growth and cancer.

<span class="mw-page-title-main">GJD3</span> Protein-coding gene in the species Homo sapiens

Gap junction delta-2 (GJD2), also known as connexin-36 (Cx36) or gap junction alpha-9 (GJA9), is a protein that in humans is encoded by the GJD2 gene.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

<span class="mw-page-title-main">Rotigaptide</span> Chemical compound

Rotigaptide (ZP-123) is a drug under clinical investigation for the treatment of cardiac arrhythmias – specifically atrial fibrillation. It is a peptide analog that has been shown to increase gap junction intercellular conductance in cardiac muscle cells. Gap junctions are protein channels that are responsible for conducting electrical impulses between cells in the heart to maintain normal rhythm. Gap junction modulation is a promising and novel mechanism of action for the treatment of cardiovascular disorders. Its peptide sequence is Ac-D-Tyr-D-Pro-D-Hyp-Gly-D-Ala-Gly-NH2.

<span class="mw-page-title-main">Gap junction modulation</span>

Gap junction modulation describes the functional manipulation of gap junctions, specialized channels that allow direct electrical and chemical communication between cells without exporting material from the cytoplasm. Gap junctions play an important regulatory role in various physiological processes including signal propagation in cardiac muscles and tissue homeostasis of the liver. Modulation is required, since gap junctions must respond to their environment, whether through an increased expression or permeability. Impaired or altered modulation can have significant health implications and are associated with the pathogenesis of the liver, heart and intestines.

References

  1. 1 2 3 4 5 Cheung, Giselle; Chever, Oana; Rouach, Nathalie (2014-11-04). "Connexons and Pannexons: Newcomers in Neurophysiology". Frontiers in Cellular Neuroscience. 8: 348. doi: 10.3389/fncel.2014.00348 . PMC   4219455 . PMID   25408635.
  2. 1 2 3 4 5 6 7 8 9 10 11 Herve, Jean-Claude; Derangeon, Mickael (2012-09-01). "Gap-junction-mediated cell-to-cell communication". Cell and Tissue Research. 352 (1): 21–31. doi:10.1007/s00441-012-1485-6. PMID   22940728. S2CID   176666.
  3. ↑ Ruiz-Meana, M.; Rodríguez-Sinovas, A.; Cabestrero, A.; Boengler, K.; Heusch, G.; Garcia-Dorado, D. (2008). "Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia-reperfusion injury". Cardiovascular Research. 77 (2): 325–333. doi: 10.1093/cvr/cvm062 . PMID   18006437.
  4. 1 2 3 4 5 Wright, Josephine; Richards, Toby; Becker, David (2012-03-01). "Connexins And Diabetes". Cardiology Research and Practice. 2012: 496904. doi: 10.1155/2012/496904 . PMC   3303578 . PMID   22536530.
  5. 1 2 3 4 5 6 7 8 9 Thevenin, Anastasia F (2013-03-07). "Proteins and Mechanisms Regulating Gap-Junction Assembly, Internalization, and Degradation". Physiology. 28 (2): 93–116. doi:10.1152/physiol.00038.2012. PMC   3768091 . PMID   23455769.
  6. ↑ Lauf, Undine; Giepmans, Ben N. G.; Lopez, Patricia; Braconnot, Sébastien; Chen, Shu-Chih; Falk, Matthias M. (6 August 2002). "Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells". Proceedings of the National Academy of Sciences. 99 (16): 10446–10451. doi: 10.1073/pnas.162055899 . PMC   124935 . PMID   12149451.
  7. ↑ Hervé, Jean-Claude (2013). "The communicating junctions, roles and dysfunctions". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1828 (1): 1–3. doi: 10.1016/j.bbamem.2012.10.012 . PMID   23088917.
  8. 1 2 3 Tomaselli, Gordon F. (2010-12-04). "Oxidant stress derails the cardiac connexon connection". Journal of Clinical Investigation. 120 (1): 87–89. doi:10.1172/jci41780. PMC   2798705 . PMID   20038808.
  9. 1 2 Zhang, Yan; Wang, Hongtao; Kovacs, Attila; Kanter, Evelyn; Yamada, Kathryn (2010-02-01). "Reduced expression of Cx43 attenuates ventricular remodeling after myocardial infarction via impaired TGF-β signaling". American Journal of Physiology. Heart and Circulatory Physiology. 298 (2): H477-87. doi:10.1152/ajpheart.00806.2009. PMC   2822575 . PMID   19966054.

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