Gap junction alpha-1 protein (GJA1), also known as connexin 43 (Cx43), is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''GJA1''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
on chromosome 6.
As a
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, form gap junctions in invertebrates. Ea ...
, GJA1 is a component of
gap junctions, which allow for gap junction
intercellular communication (GJIC) between
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
s to regulate
cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as d ...
,
proliferation, and
differentiation.
As a result of its function, GJA1 is implicated in many biological processes, including
muscle contraction
Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as ...
,
embryonic development,
inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
, and
spermatogenesis, as well as
disease
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
s, including
oculodentodigital dysplasia (ODDD), heart malformations, and
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s.
Structure
GJA1 is a 43.0 kDa
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
composed of 382
amino acids. GJA1 contains a long
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
tail, an
N-terminal domain, and multiple
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...
domains. The protein passes through the
phospholipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
four times, leaving its C- and N-terminals exposed to the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
.
The C-terminal tail is composed of 50
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
s and includes
post-translational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribos ...
sites, as well as binding sites for
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s,
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is com ...
elements, and other proteins.
As a result, the C-terminal tail is central to functions such as regulating pH gating and channel assembly. Notably, the DNA region of the ''GJA1'' gene encoding this tail is highly conserved, indicating that it is either resistant to mutations or becomes lethal when mutated. Meanwhile, the N-terminal domain is involved in channel gating and oligomerization and, thus, may control the switch between the channel's open and closed states. The transmembrane domains form the gap junction channel while the
extracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
loops facilitate proper channel docking. Moreover, two extracellular loops form disulfide bonds that interact with two hexamers to form a complete gap junction channel.
The connexin-43 internal ribosome entry site is an
RNA element present in the
5' UTR
The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of t ...
of the
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
of GJA1. This
internal ribosome entry site An internal ribosome entry site, abbreviated IRES, is an RNA element that allows for translation initiation in a cap-independent manner, as part of the greater process of protein synthesis. In eukaryotic translation, initiation typically occurs at ...
(IRES) allows cap independent
translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
during conditions such as
heat shock
The heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a normal ...
and stress.
Function
![Microphotograph of connexin 43 distribution in the rat myocardium](https://upload.wikimedia.org/wikipedia/commons/3/36/Microphotograph_of_connexin_43_distribution_in_the_rat_myocardium.jpg)
As a member of the
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, form gap junctions in invertebrates. Ea ...
family, GJA1 is a component of
gap junctions, which are intercellular channels that connect adjacent cells to permit the exchange of low molecular weight molecules, such as small
ions
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
and
secondary messenger
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 or cell signaling, encompassing both first m ...
s, to maintain
homeostasis
In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
.
GJA1 is the most ubiquitously expressed connexin and is detected in most cell types.
It is the major protein in
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
gap junctions and is purported to play a crucial role in the synchronized contraction of the heart.
Despite its key role in the heart and other vital organs, GJA1 has a short
half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
(only two to four hours), indicating that the protein undergoes daily
turnover in the heart and may be highly abundant or compensated with other connexins.
GJA1 is also largely involved in
embryonic development.
For instance,
transforming growth factor-beta 1 (TGF-β1) was observed to induce GJA1 expression via the
Smad and
ERK1
Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene.
Function
The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) fami ...
/2
signaling pathway
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellul ...
s, resulting in
trophoblast
The trophoblast (from Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the p ...
cell differentiation into the
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
.
Furthermore, GJA1 is expressed in many
immune cells
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
, such as
eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s and
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s, where its gap junction function promotes the maturation and activation of these cells and, by extension, the cross-communication necessary to mount an
inflammatory response.
In addition, GJA1 can be found in the
Leydig cell
Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...
s and
seminiferous tubules
Seminiferous tubules are located within the testes, and are the specific location of meiosis, and the subsequent creation of male gametes, namely spermatozoa. Structure
The epithelium of the tubule consists of a type of sustentacular cells known ...
between
Sertoli cell
Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-stimu ...
s and
spermatogonia
A spermatogonium (plural: ''spermatogonia'') is an undifferentiated male germ cell. Spermatogonia undergo spermatogenesis to form mature spermatozoa in the seminiferous tubules of the testis.
There are three subtypes of spermatogonia in humans:
...
or
primary spermatocytes, where it plays a key role in
spermatogenesis and
testis
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
development through controlling the
tight junction
Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...
proteins in the
blood-testis barrier.
While it is a channel protein, GJA1 can also perform channel-independent functions. In the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
, the protein regulates the
microtubule network and, by extension,
cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular dire ...
and
polarity.
This function has been observed in
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
and heart development, as well as wound-healing in
endothelial
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
cells.
GJA1 has also been observed to localize to the mitochondria, where it promotes cell survival by downregulating the intrinsic apoptotic pathway during conditions of oxidative stress.
Clinical significance
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s in this gene have been associated with ODDD;
craniometaphyseal dysplasia;
sudden infant death syndrome
Sudden infant death syndrome (SIDS) is the sudden unexplained death of a child of less than one year of age. Diagnosis requires that the death remain unexplained even after a thorough autopsy and detailed death scene investigation. SIDS usuall ...
, which is linked to cardiac
arrhythmia;
Hallermann–Streiff syndrome
Hallermann–Streiff syndrome is a congenital disorder that affects growth, cranial development, hair-growth, and dental development. There are fewer than 200 people with the syndrome worldwide. One notable organization that is supporting peopl ...
; and heart malformations, such as
viscero-atrial heterotaxia.
There have also been a few cases of reported hearing loss and skin disorders unrelated to ODDD.
Ultimately, GJA1 has low tolerance for deviations from its original sequence, with mutations resulting in loss- or gain-of-channel function that lead to disease phenotypes.
It is paradoxical, however, that patients with an array of somatic mutations in ''GJA1'' most often do not present with cardiac
arrhythmias, even though connexin-43 is the most abundant protein forming
gap junctional pores in
cardiomyocyte
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
s and are essential for normal
action potential
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
propagation.
Notably, GJA1 expression has been associated with a wide variety of cancers, including
nasopharyngeal carcinoma
Nasopharyngeal carcinoma (NPC), or nasopharynx cancer, is the most common cancer originating in the nasopharynx, most commonly in the postero-lateral nasopharynx or pharyngeal recess ( fossa of Rosenmüller), accounting for 50% of cases. NPC occurs ...
,
meningioma,
hemangiopericytoma,
liver tumor
Liver tumors (also known as hepatic tumors) are abnormal growth of liver cells on or in the liver. Several distinct types of tumors can develop in the liver because the liver is made up of various cell types. Liver tumors can be classified as beni ...
,
colon cancer,
esophageal cancer,
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
,
mesothelioma
Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium). The most common area affected is the lining of the lungs and chest wall. Less commonly the lining ...
,
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...
,
lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malign ...
,
adrenocortical tumors,
renal cell cancer
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, res ...
,
cervical carcinoma
Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...
,
ovarian carcinoma
Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different cel ...
,
endometrial carcinoma
Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body. The first sign is most o ...
,
prostate cancer,
thyroid carcinoma, and
testicular cancer
Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system. Symptoms may include a lump in the testicle, or swelling or pain in the scrotum. Treatment may result in infertility.
Risk factors include an ...
.
Its role in controlling cell motility and polarity was thought to contribute to cancer development and
metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...
, though its role as a gap junction protein may also be involved.
Moreover, the cytoprotective effects of this protein can promote tumor cell survival in
radiotherapy treatments, while silencing its gene increases radiosensitivity. As a result, GJA1 may serve as a target for improving the success of radiotherapeutic treatment of cancer.
As a biomarker, GJA1 could also be used to screen young males for risk of testis cancer.
The
thyroid hormone triiodothyronine
Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.
Production of T3 and its prohormone thyroxine ...
(T3) downregulates the expression of GJA1. This is assumed to be a key mechanism why the conduction velocity in myocardial tissue is reduced in
thyrotoxicosis
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. ...
, thereby promoting
cardiac arrhythmia
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
.
Currently, only
rotigaptide, an antiarrhythmic peptide-based drug, and its
derivative
In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...
s, such as
danegaptide, have reached clinical trials for treating cardiac pathologies by enhancing GJA1 expression. Alternatively, drugs could target complementary connexins, such as
Cx40, which function similarly to GJA1. However, both approaches still require a system to target the diseased tissue to avoid inducing developmental abnormalities elsewhere.
Thus, a more effective approach entails designing a
miRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miR ...
through
antisense
In molecular biology and genetics, the sense of a nucleic acid molecule, particularly of a strand of DNA or RNA, refers to the nature of the roles of the strand and its complement in specifying a sequence of amino acids. Depending on the context ...
oligonucleotides,
transfection
Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: " transformation" is typically used to des ...
, or
infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...
to knock down only mutant GJA1 mRNA, thus allowing the expression of
wildtype
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...
GJA1 and retaining normal
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...
.
Interactions
Gap junction protein, alpha 1 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
Cx37,
*
Cx40,
*
Cx45,
*
MAPK7
Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the ''MAPK7'' gene.
Function
MAPK7 is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...
,
*
Caveolin 1
Caveolin-1 is a protein that in humans is encoded by the ''CAV1'' gene.
Function
The scaffolding protein encoded by this gene is the main component of the caveolae plasma membranes found in most cell types. The protein links integrin subunits ...
,
*
Tight junction protein 1
Zonula occludens-1 ZO-1, also known as Tight junction protein-1 is a 220-kD peripheral membrane protein that is encoded by the ''TJP1'' gene in humans. It belongs to the family of ''zonula occludens proteins'' (ZO-1, ZO-2, and ZO-3), which are ti ...
*
CSNK1D
Casein kinase I isoform delta also known as CKI-delta or CK1δ is an enzyme that in humans is encoded by the gene ''CSNK1D'', which is located on chromosome 17 (17q25.3). It is a member of the CK1 (formerly named casein kinase 1) family of serine ...
,
and
*PTPmu (
PTPRM
Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the ''PTPRM'' gene.
Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Protein tyrosine phosphatases a ...
).
See also
*
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, form gap junctions in invertebrates. Ea ...
*
Hypoplastic left heart syndrome
Hypoplastic left heart syndrome (HLHS) is a rare congenital heart defect in which the left side of the heart is severely underdeveloped and incapable of supporting the systemic circulation. It is estimated to account for 2-3% of all congenital hea ...
References
Further reading
*
*
External links
*
{{Ion channels, g4
Cis-regulatory RNA elements
Connexins