GJA1

Last updated

GJA1
Protein GJA1 PDB 1r5s.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GJA1 , AVSD3, CMDR, CX43, EKVP, GJAL, HLHS1, HSS, ODDD, PPKCA, gap junction protein alpha 1, EKVP3
External IDs OMIM: 121014; MGI: 95713; HomoloGene: 136; GeneCards: GJA1; OMA:GJA1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2697

14609

Ensembl

ENSG00000152661

ENSMUSG00000050953

UniProt

P17302

P23242

RefSeq (mRNA)

NM_000165

NM_010288

RefSeq (protein)

NP_000156

NP_034418

Location (UCSC) Chr 6: 121.44 – 121.45 Mb Chr 10: 56.25 – 56.28 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Connexin43
PDB 1r5s EBI.jpg
connexin 43 carboxyl terminal domain
Identifiers
SymbolConnexin43
Pfam PF03508
InterPro IPR013124
TCDB 1.A.24
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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. [5] [6] [7] 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. [8] 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. [7] [9] [10]

Contents

Structure

GJA1 is a 43.0 kDa protein composed of 382 amino acids. [11] GJA1 contains a long C-terminal tail, an N-terminal domain, and multiple transmembrane domains. The protein passes through the phospholipid bilayer four times, leaving its C- and N-terminals exposed to the cytoplasm. [12] The C-terminal tail is composed of 50 amino acids and includes post-translational modification sites, as well as binding sites for transcription factors, cytoskeleton elements, and other proteins. [12] [13] 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 loops facilitate proper channel docking. Moreover, two extracellular loops form disulfide bonds that interact with two hexamers to form a complete gap junction channel. [12]

The connexin-43 internal ribosome entry site is an RNA element present in the 5' UTR of the mRNA of GJA1. This internal ribosome entry site (IRES) allows cap independent translation during conditions such as heat shock and stress. [14]

Connexin-43 internal ribosome entry site (IRES)
RF00487.jpg
Predicted secondary structure and sequence conservation of IRES_Cx43
Identifiers
SymbolIRES_Cx43
Rfam RF00487
Other data
RNA type Cis-reg; IRES
Domain(s) Eukaryota
GO GO:0043022
SO SO:0000243
PDB structures PDBe

Function

Connexin 43 distribution in the rat myocardium (gap junctions between cardiomyocytes) Microphotograph of connexin 43 distribution in the rat myocardium.jpg
Connexin 43 distribution in the rat myocardium (gap junctions between cardiomyocytes)

As a member of the connexin 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 and secondary messengers, to maintain homeostasis. [7] [12] [15]

GJA1 is the most ubiquitously expressed connexin and is detected in most cell types. [7] [9] [12] It is the major protein in heart gap junctions and is purported to play a crucial role in the synchronized contraction of the heart. [7] Despite its key role in the heart and other vital organs, GJA1 has a short half-life (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. [12] GJA1 is also largely involved in embryonic development. [7] [8] For instance, transforming growth factor-beta 1 (TGF-β1) was observed to induce GJA1 expression via the Smad and ERK1/2 signaling pathways, resulting in trophoblast cell differentiation into the placenta. [8]

Furthermore, GJA1 is expressed in many immune cells, such as eosinophils and T cells, 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. [10] It has also been shown that uterine macrophage directly physically couple with uterine myocytes through GJA1, transferring Ca²⁺, to promote uterine muscle contraction and excitation during human labor onset. [16]

In addition, GJA1 can be found in the Leydig cells and seminiferous tubules between Sertoli cells and spermatogonia or primary spermatocytes, where it plays a key role in spermatogenesis and testis development through controlling the tight junction proteins in the blood-testis barrier.

While it is a channel protein, GJA1 can also perform channel-independent functions. In the cytoplasm, the protein regulates the microtubule network and, by extension, cell migration and polarity. [9] [13] This function has been observed in brain and heart development, as well as wound-healing in endothelial cells. [13] 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. [15]

Clinical significance

Mutations in this gene have been associated with ODDD; craniometaphyseal dysplasia; sudden infant death syndrome, which is linked to cardiac arrhythmia; Hallermann–Streiff syndrome; and heart malformations, such as viscero-atrial heterotaxia. [7] [9] [12] [17] There have also been a few cases of reported hearing loss and skin disorders unrelated to ODDD. [12] 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. [12] 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 cardiomyocytes and are essential for normal action potential propagation. [18]

Notably, GJA1 expression has been associated with a wide variety of cancers, including nasopharyngeal carcinoma, meningioma, hemangiopericytoma, liver tumor, colon cancer, esophageal cancer, breast cancer, mesothelioma, glioblastoma, lung cancer, adrenocortical tumors, renal cell cancer, cervical carcinoma, ovarian carcinoma, endometrial carcinoma, prostate cancer, thyroid carcinoma, and testicular cancer. [9] Its role in controlling cell motility and polarity was thought to contribute to cancer development and metastasis, though its role as a gap junction protein may also be involved. [9] [15] 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. [15] As a biomarker, GJA1 could also be used to screen young males for risk of testis cancer. [9]

The thyroid hormone triiodothyronine (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, thereby promoting cardiac arrhythmia. [19]

Currently, only rotigaptide, an antiarrhythmic peptide-based drug, and its derivatives, 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. [12] Thus, a more effective approach entails designing a miRNA through antisense oligonucleotides, transfection, or infection to knock down only mutant GJA1 mRNA, thus allowing the expression of wildtype GJA1 and retaining normal phenotype. [9] [12]

Interactions

Gap junction protein, alpha 1 has been shown to interact with:

See also

Related Research Articles

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

Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances. Substances exchanged include small molecules, substrates, and metabolites.

<span class="mw-page-title-main">Connexon</span> Protein hexamer that forms the pore of gap junctions between cells

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. 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.

<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, forms 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">Desmoglein-2</span> Protein found in humans

Desmoglein-2 is a protein that in humans is encoded by the DSG2 gene. Desmoglein-2 is highly expressed in epithelial cells and cardiomyocytes. Desmoglein-2 is localized to desmosome structures at regions of cell-cell contact and functions to structurally adhere adjacent cells together. In cardiac muscle, these regions are specialized regions known as intercalated discs. Mutations in desmoglein-2 have been associated with arrhythmogenic right ventricular cardiomyopathy and familial dilated cardiomyopathy.

<span class="mw-page-title-main">KCNE2</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21. MiRP1 is a voltage-gated potassium channel accessory subunit associated with Long QT syndrome. It is ubiquitously expressed in many tissues and cell types. Because of this and its ability to regulate multiple different ion channels, KCNE2 exerts considerable influence on a number of cell types and tissues. Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellular N-terminal and intracellular C-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias. The KCNE2 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.

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

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit is a member of the AGC kinase family, and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.

<span class="mw-page-title-main">GJB2</span> Protein-coding gene in the species Homo sapiens

Gap junction beta-2 protein (GJB2), also known as connexin 26 (Cx26) — is a protein that in humans is encoded by the GJB2 gene.

<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">Cadherin-2</span> Protein found in humans

Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the CDH2 gene. CDH2 has also been designated as CD325 . Cadherin-2 is a transmembrane protein expressed in multiple tissues and functions to mediate cell–cell adhesion. In cardiac muscle, Cadherin-2 is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. Alterations in expression and integrity of Cadherin-2 has been observed in various forms of disease, including human dilated cardiomyopathy. Variants in CDH2 have also been identified to cause a syndromic neurodevelopmental disorder.

<span class="mw-page-title-main">GJA5</span> Protein-coding gene in the species Homo sapiens

Gap junction alpha-5 protein (GJA5), also known as connexin 40 (Cx40) — is a protein that in humans is encoded by the GJA5 gene.

<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">GJB3</span> Mammalian protein found in Homo sapiens

Gap junction beta-3 protein (GJB3), also known as connexin 31 (Cx31) — is a protein that in humans is encoded by the GJB3 gene.

<span class="mw-page-title-main">GJA4</span> Protein-coding gene in the species Homo sapiens

Gap junction alpha-4 protein, also known as Connexin-37 or Cx37, is a protein that in humans is encoded by the GJA4 gene. This protein, like other Connexin proteins, forms connections between cells known as gap junctions. Connexin 37 can be found in many tissues including the ovary, heart, and kidney.

<span class="mw-page-title-main">Plakophilin-2</span> Protein-coding gene in the species Homo sapiens

Plakophilin-2 is a protein that in humans is encoded by the PKP2 gene. Plakophilin 2 is expressed in skin and cardiac muscle, where it functions to link cadherins to intermediate filaments in the cytoskeleton. In cardiac muscle, plakophilin-2 is found in desmosome structures located within intercalated discs. Mutations in PKP2 have been shown to be causal in arrhythmogenic right ventricular cardiomyopathy.

<span class="mw-page-title-main">GJC1</span> Protein-coding gene in the species Homo sapiens

Gap junction gamma-1 protein (GJC1), also known as gap junction alpha-7 protein (GJA7) and connexin 45 (Cx45) — is a protein that in humans is encoded by the GJC1 gene.

<span class="mw-page-title-main">GJA8</span> Protein-coding gene in the species Homo sapiens

Gap junction alpha-8 protein is a protein that in humans is encoded by the GJA8 gene. It is also known as connexin 50.

<span class="mw-page-title-main">Oculodentodigital dysplasia</span> Medical condition

Oculodentodigital syndrome is an extremely rare genetic condition that typically results in small eyes, underdeveloped teeth, and syndactyly and malformation of the fourth and fifth fingers. It is considered a kind of ectodermal dysplasia.

<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.

<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.

A gap junction modulator is a compound or agent that either facilitates or inhibits the transfer of small molecules between biological cells by regulating gap junctions. Various physiological processes including cardiac, neural or auditory, depend on gap junctions to perform crucial regulatory roles, and the modulators themselves are the key players in this procedure. Gap junctions are necessary for diffusion of small molecules from cell to cell, keeping the cells interlinked and connecting the cytoplasm, allowing transfer of signals or resources between the body.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000152661 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000050953 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Boyadjiev SA, Jabs EW, LaBuda M, Jamal JE, Torbergsen T, Ptácek LJ, Rogers RC, Nyberg-Hansen R, Opjordsmoen S, Zeller CB, Stine OC, Stalker HJ, Zori RT, Shapiro RE (May 1999). "Linkage analysis narrows the critical region for oculodentodigital dysplasia to chromosome 6q22-q23". Genomics. 58 (1): 34–40. doi:10.1006/geno.1999.5814. PMID   10331943.
  6. ↑ Fishman GI, Eddy RL, Shows TB, Rosenthal L, Leinwand LA (May 1991). "The human connexin gene family of gap junction proteins: distinct chromosomal locations but similar structures". Genomics. 10 (1): 250–256. doi:10.1016/0888-7543(91)90507-B. PMID   1646158.
  7. 1 2 3 4 5 6 7 "Entrez Gene: GJA1 gap junction protein, alpha 1, 43kDa".
  8. 1 2 3 Cheng JC, Chang HM, Fang L, Sun YP, Leung PC (Jul 2015). "TGF-β1 up-regulates connexin43 expression: a potential mechanism for human trophoblast cell differentiation". Journal of Cellular Physiology. 230 (7): 1558–1566. doi:10.1002/jcp.24902. PMID   25560303. S2CID   28968035.
  9. 1 2 3 4 5 6 7 8 Chevallier D, Carette D, Segretain D, Gilleron J, Pointis G (Apr 2013). "Connexin 43 a check-point component of cell proliferation implicated in a wide range of human testis diseases". Cellular and Molecular Life Sciences. 70 (7): 1207–1220. doi:10.1007/s00018-012-1121-3. PMC   11113700 . PMID   22918484. S2CID   11855947.
  10. 1 2 Vliagoftis H, Ebeling C, Ilarraza R, Mahmudi-Azer S, Abel M, Adamko D, Befus AD, Moqbel R (2014). "Connexin 43 expression on peripheral blood eosinophils: role of gap junctions in transendothelial migration". BioMed Research International. 2014: 803257. doi: 10.1155/2014/803257 . PMC   4109672 . PMID   25110696.
  11. ↑ "Protein sequence of human GJA1 (Uniprot ID: P17302)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 5 October 2015. Retrieved 18 September 2015.
  12. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Laird DW (Apr 2014). "Syndromic and non-syndromic disease-linked Cx43 mutations". FEBS Letters. 588 (8): 1339–1348. Bibcode:2014FEBSL.588.1339L. doi: 10.1016/j.febslet.2013.12.022 . PMID   24434540. S2CID   20651016.
  13. 1 2 3 Kameritsch P, Pogoda K, Pohl U (Aug 2012). "Channel-independent influence of connexin 43 on cell migration". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1818 (8): 1993–2001. doi: 10.1016/j.bbamem.2011.11.016 . PMID   22155212.
  14. ↑ Schiavi A, Hudder A, Werner R (Dec 1999). "Connexin43 mRNA contains a functional internal ribosome entry site". FEBS Letters. 464 (3): 118–122. Bibcode:1999FEBSL.464..118S. doi: 10.1016/S0014-5793(99)01699-3 . PMID   10618489. S2CID   26020820.
  15. 1 2 3 4 Ghosh S, Kumar A, Chandna S (Jul 2015). "Connexin-43 downregulation in G2/M phase enriched tumour cells causes extensive low-dose hyper-radiosensitivity (HRS) associated with mitochondrial apoptotic events". Cancer Letters. 363 (1): 46–59. doi:10.1016/j.canlet.2015.03.046. PMID   25843295.
  16. ↑ Boros-Rausch, A., Shynlova, O., & Lye, S. J. (2021). "A Broad-Spectrum Chemokine Inhibitor Blocks Inflammation-Induced Myometrial Myocyte-Macrophage Crosstalk and Myometrial Contraction". Cells. 11 (1): 128. doi: 10.3390/cells11010128 PMID 35011690
  17. ↑ Pizzuti A, Flex E, Mingarelli R, Salpietro C, Zelante L, Dallapiccola B (Mar 2004). "A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype". Human Mutation. 23 (3): 286. doi: 10.1002/humu.9220 . PMID   14974090. S2CID   13345970.
  18. ↑ Delmar M, Makita N (May 2012). "Cardiac connexins, mutations and arrhythmias". Current Opinion in Cardiology. 27 (3): 236–241. doi:10.1097/HCO.0b013e328352220e. PMID   22382502. S2CID   205620477.
  19. ↑ Müller P, Leow MK, Dietrich JW (2022). "Minor perturbations of thyroid homeostasis and major cardiovascular endpoints-Physiological mechanisms and clinical evidence". Frontiers in Cardiovascular Medicine. 9: 942971. doi: 10.3389/fcvm.2022.942971 . PMC   9420854 . PMID   36046184.
  20. ↑ Cameron SJ, Malik S, Akaike M, Lerner-Marmarosh N, Yan C, Lee JD, Abe J, Yang J (May 2003). "Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation". The Journal of Biological Chemistry. 278 (20): 18682–18688. doi: 10.1074/jbc.M213283200 . PMID   12637502.
  21. ↑ Schubert AL, Schubert W, Spray DC, Lisanti MP (May 2002). "Connexin family members target to lipid raft domains and interact with caveolin-1". Biochemistry. 41 (18): 5754–5764. doi:10.1021/bi0121656. PMID   11980479.
  22. ↑ Giepmans BN, Moolenaar WH (1998). "The gap junction protein connexin43 interacts with the second PDZ domain of the zona occludens-1 protein". Current Biology. 8 (16): 931–934. Bibcode:1998CBio....8..931G. doi: 10.1016/S0960-9822(07)00375-2 . PMID   9707407. S2CID   6434044.
  23. ↑ Cooper CD, Lampe PD (Nov 2002). "Casein kinase 1 regulates connexin-43 gap junction assembly". The Journal of Biological Chemistry. 277 (47): 44962–44968. doi: 10.1074/jbc.M209427200 . PMID   12270943.
  24. ↑ Giepmans BN, Feiken E, Gebbink MF, Moolenaar WH (2003). "Association of connexin43 with a receptor protein tyrosine phosphatase". Cell Communication & Adhesion. 10 (4–6): 201–205. doi: 10.1080/cac.10.4-6.201.205 . PMID   14681016.

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