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Cellular and Molecular Life Sciences :... Feb 2020Gap junctions consist of arrays of intercellular channels that enable adjacent cells to communicate both electrically and metabolically. Gap junctions have a wide... (Review)
Review
Gap junctions consist of arrays of intercellular channels that enable adjacent cells to communicate both electrically and metabolically. Gap junctions have a wide diversity of physiological functions, playing critical roles in both excitable and non-excitable tissues. Gap junction channels are formed by integral membrane proteins called connexins. Inherited or acquired alterations in connexins are associated with numerous diseases, including heart failure, neuropathologies, deafness, skin disorders, cataracts and cancer. Gap junctions are highly dynamic structures and by modulating the turnover rate of connexins, cells can rapidly alter the number of gap junction channels at the plasma membrane in response to extracellular or intracellular cues. Increasing evidence suggests that ubiquitination has important roles in the regulation of endoplasmic reticulum-associated degradation of connexins as well as in the modulation of gap junction endocytosis and post-endocytic sorting of connexins to lysosomes. In recent years, researchers have also started to provide insights into the physiological roles of connexin ubiquitination in specific tissue types. This review provides an overview of the advances made in understanding the roles of connexin ubiquitination in the regulation of gap junction intercellular communication and discusses the emerging physiological and pathophysiological implications of these processes.
Topics: Animals; Cataract; Cell Communication; Connexin 43; Connexins; Gap Junctions; Heart Diseases; Humans; Neoplasms; Protein Processing, Post-Translational; Ubiquitination
PubMed: 31501970
DOI: 10.1007/s00018-019-03285-0 -
Seizure Jan 2021The astroglial network connected through gap junctions assembling from connexins physiologically balances the concentrations of ions and neurotransmitters around... (Review)
Review
The astroglial network connected through gap junctions assembling from connexins physiologically balances the concentrations of ions and neurotransmitters around neurons. Astrocytic dysfunction has been associated with many neurological disorders including epilepsy. Dissociated gap junctions result in the increased activity of connexin hemichannels which triggers brain pathophysiological changes. Previous studies in patients and animal models of epilepsy indicate that the reduced gap junction coupling from assembled connexin hemichannels in the astrocytes may play an important role in epileptogenesis. This abnormal cell-to-cell communication is now emerging as an important feature of brain pathologies and being considered as a novel therapeutic target for controlling epileptogenesis. In particular, candidate drugs with ability of inhibition of connexin hemichannel activity and enhancement of gap junction formation in astrocytes should be explored to prevent epileptogenesis and control epilepsy.
Topics: Animals; Astrocytes; Cell Communication; Connexins; Gap Junctions; Humans; Neurons
PubMed: 33348235
DOI: 10.1016/j.seizure.2020.11.022 -
Comprehensive Physiology Jul 2012Gap junctions are essential to the function of multicellular animals, which require a high degree of coordination between cells. In vertebrates, gap junctions comprise... (Review)
Review
Gap junctions are essential to the function of multicellular animals, which require a high degree of coordination between cells. In vertebrates, gap junctions comprise connexins and currently 21 connexins are known in humans. The functions of gap junctions are highly diverse and include exchange of metabolites and electrical signals between cells, as well as functions, which are apparently unrelated to intercellular communication. Given the diversity of gap junction physiology, regulation of gap junction activity is complex. The structure of the various connexins is known to some extent; and structural rearrangements and intramolecular interactions are important for regulation of channel function. Intercellular coupling is further regulated by the number and activity of channels present in gap junctional plaques. The number of connexins in cell-cell channels is regulated by controlling transcription, translation, trafficking, and degradation; and all of these processes are under strict control. Once in the membrane, channel activity is determined by the conductive properties of the connexin involved, which can be regulated by voltage and chemical gating, as well as a large number of posttranslational modifications. The aim of the present article is to review our current knowledge on the structure, regulation, function, and pharmacology of gap junctions. This will be supported by examples of how different connexins and their regulation act in concert to achieve appropriate physiological control, and how disturbances of connexin function can lead to disease.
Topics: Amino Acid Sequence; Animals; Cell Communication; Connexins; Gap Junctions; Gene Expression Regulation; Humans; Molecular Sequence Data; Protein Conformation; Protein Processing, Post-Translational; Protein Transport
PubMed: 23723031
DOI: 10.1002/cphy.c110051 -
International Journal of Molecular... May 2019Gap junction (GJ) channels in invertebrates have been used to understand cell-to-cell communication in vertebrates. GJs are a common form of intercellular communication... (Review)
Review
Gap junction (GJ) channels in invertebrates have been used to understand cell-to-cell communication in vertebrates. GJs are a common form of intercellular communication channels which connect the cytoplasm of adjacent cells. Dysregulation and structural alteration of the gap junction-mediated communication have been proven to be associated with a myriad of symptoms and tissue-specific pathologies. Animal models relying on the invertebrate nervous system have exposed a relationship between GJs and the formation of electrical synapses during embryogenesis and adulthood. The modulation of GJs as a therapeutic and clinical tool may eventually provide an alternative for treating tissue formation-related diseases and cell propagation. This review concerns the similarities between innexins and human connexins from nucleotide and protein sequence level perspectives. It also sets forth evidence of computational techniques applied to the study of proteins, sequences, and molecular dynamics. Furthermore, we propose machine learning techniques as a method that could be used to study protein structure, gap junction inhibition, metabolism, and drug development.
Topics: Animals; Computer Simulation; Connexins; Gap Junctions; Humans; Machine Learning; Models, Biological; Nervous System; Protein Conformation
PubMed: 31109150
DOI: 10.3390/ijms20102476 -
Biochimica Et Biophysica Acta.... Jan 2018Gap junction channels facilitate the intercellular exchange of ions and small molecules. While this process is critical to all multicellular organisms, the proteins that... (Review)
Review
Gap junction channels facilitate the intercellular exchange of ions and small molecules. While this process is critical to all multicellular organisms, the proteins that form gap junction channels are not conserved. Vertebrate gap junctions are formed by connexins, while invertebrate gap junctions are formed by innexins. Interestingly, vertebrates and lower chordates contain innexin homologs, the pannexins, which also form channels, but rarely (if ever) make intercellular channels. While the connexin and the innexin/pannexin polypeptides do not share significant sequence similarity, all three of these protein families share a similar membrane topology and some similarities in quaternary structure. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.
Topics: Animals; Connexins; Gap Junctions; Humans; Ion Transport
PubMed: 28559187
DOI: 10.1016/j.bbamem.2017.05.016 -
International Journal of Molecular... Sep 2018This Special Issue relates to the 18th biannual International Gap Junction Conference (IGJC2017), held at the Crowne Plaza Hotel, Glasgow, U.K., from the 29 July⁻2...
This Special Issue relates to the 18th biannual International Gap Junction Conference (IGJC2017), held at the Crowne Plaza Hotel, Glasgow, U.K., from the 29 July⁻2 August 2017 [...].
Topics: Carcinogenesis; Congresses as Topic; Connexins; Gap Junctions; Humans; Protein Interaction Maps; Translational Research, Biomedical; United Kingdom; Wound Healing
PubMed: 30231591
DOI: 10.3390/ijms19092823 -
International Journal of Molecular... Apr 2022Inherited diseases caused by connexin mutations are found in multiple organs and include hereditary deafness, congenital cataract, congenital heart diseases, hereditary... (Review)
Review
Inherited diseases caused by connexin mutations are found in multiple organs and include hereditary deafness, congenital cataract, congenital heart diseases, hereditary skin diseases, and X-linked Charcot-Marie-Tooth disease (CMT1X). A large number of knockout and knock-in animal models have been used to study the pathology and pathogenesis of diseases of different organs. Because the structures of different connexins are highly homologous and the functions of gap junctions formed by these connexins are similar, connexin-related hereditary diseases may share the same pathogenic mechanism. Here, we analyze the similarities and differences of the pathology and pathogenesis in animal models and find that connexin mutations in gap junction genes expressed in the ear, eye, heart, skin, and peripheral nerves can affect cellular proliferation and differentiation of corresponding organs. Additionally, some dominant mutations (e.g., Cx43 p.Gly60Ser, Cx32 p.Arg75Trp, Cx32 p.Asn175Asp, and Cx32 p.Arg142Trp) are identified as gain-of-function variants in vivo, which may play a vital role in the onset of dominant inherited diseases. Specifically, patients with these dominant mutations receive no benefits from gene therapy. Finally, the complete loss of gap junctional function or altered channel function including permeability (ions, adenosine triphosphate (ATP), Inositol 1,4,5-trisphosphate (IP3), Ca, glucose, miRNA) and electric activity are also identified in vivo or in vitro.
Topics: Animals; Charcot-Marie-Tooth Disease; Connexin 26; Connexins; Gap Junctions; Genes, Dominant; Humans; Mutation
PubMed: 35457072
DOI: 10.3390/ijms23084255 -
ACS Biomaterials Science & Engineering Apr 2022Cellular delivery of therapeutic macromolecules such as proteins, peptides, and nucleic acids remains limited due to inefficient transport across the cellular plasma...
Cellular delivery of therapeutic macromolecules such as proteins, peptides, and nucleic acids remains limited due to inefficient transport across the cellular plasma membrane. Gap junction channels, composed of connexin proteins, provide a mechanism for direct transfer of small molecules across membranes, and recent evidence suggests that the transfer of larger, polymer-like molecules such as microRNAs may be possible. Here, we report direct evidence of gap junction-mediated transfer of polymeric macromolecules. Specifically, we examined the transport of dextran chains with molecular weights ranging from 10 to 70 kDa. We found that dextran chains of up to 40 kDa can diffuse through at least five cell layers in a gap junction-dependent manner within a 30 min time frame. Further, we evaluated the ability of connectosomes, cell-derived vesicles containing functional connexin proteins, to be loaded with dextran chains. By opening connexon hemichannel pores within the membranes of connectosomes, we found that 10 kDa dextran was loaded into more than 90% of vesicles, with reduced levels of loading for dextran chains of larger molecular weight. Upon delivering 10 kDa dextran-loaded connectosomes to cells, we further found that connectosomes transferred these membrane-impermeable molecules to the cellular cytosol with dramatically improved efficiency in comparison to the delivery of free, unencapsulated dextran. Collectively, these results reveal that polymeric macromolecules can be delivered to cells via gap junctions, suggesting that the gap junction route may be useful for the delivery of polymeric therapeutic molecules, such as nucleic acids and peptides.
Topics: Connexins; Dextrans; Gap Junctions; Nucleic Acids; Polymers
PubMed: 35263989
DOI: 10.1021/acsbiomaterials.1c01459 -
Biomolecules Dec 2020The incidence of brain pathologies has increased during last decades. Better diagnosis (autism spectrum disorders) and longer life expectancy (Parkinson's disease,... (Review)
Review
The incidence of brain pathologies has increased during last decades. Better diagnosis (autism spectrum disorders) and longer life expectancy (Parkinson's disease, Alzheimer's disease) partly explain this increase, while emerging data suggest pollutant exposures as a possible but still underestimated cause of major brain disorders. Taking into account that the brain parenchyma is rich in gap junctions and that most pollutants inhibit their function; brain disorders might be the consequence of gap-junctional alterations due to long-term exposures to pollutants. In this article, this hypothesis is addressed through three complementary aspects: (1) the gap-junctional organization and connexin expression in brain parenchyma and their function; (2) the effect of major pollutants (pesticides, bisphenol A, phthalates, heavy metals, airborne particles, etc.) on gap-junctional and connexin functions; (3) a description of the major brain disorders categorized as neurodevelopmental (autism spectrum disorders, attention deficit hyperactivity disorders, epilepsy), neurobehavioral (migraines, major depressive disorders), neurodegenerative (Parkinson's and Alzheimer's diseases) and cancers (glioma), in which both connexin dysfunction and pollutant involvement have been described. Based on these different aspects, the possible involvement of pollutant-inhibited gap junctions in brain disorders is discussed for prenatal and postnatal exposures.
Topics: Air Pollutants; Alzheimer Disease; Brain; Brain Diseases; Cell Communication; Connexin 43; Depressive Disorder, Major; Female; Gap Junctions; Humans; Pregnancy
PubMed: 33396565
DOI: 10.3390/biom11010051 -
Neuroscience Letters Mar 2019Connexins play vital roles in hearing, including promoting cochlear development and sustaining auditory function in the mature cochlea. Mutations in connexins expressed... (Review)
Review
Connexins play vital roles in hearing, including promoting cochlear development and sustaining auditory function in the mature cochlea. Mutations in connexins expressed in the cochlear epithelium, Cx26 and Cx30, cause sensorineural deafness and in the case of Cx26, is one of the most common causes of non-syndromic, hereditary deafness. Connexins function as gap junction channels and as hemichannels, which mediate intercellular and transmembrane signaling, respectively. Both channel configurations can play important, but very different roles in the cochlea. The potential roles connexin hemichannels can play are discussed both in normal cochlear function and in promoting pathogenesis that can lead to hearing loss.
Topics: Animals; Cochlea; Connexins; Gap Junctions; Humans
PubMed: 28917982
DOI: 10.1016/j.neulet.2017.09.020