Anatomy of the Cochlea and Vestibular System: Relating Ultrastructure to Function
John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed in Paediatrics, The Ear, Skull Base, 2018
Their cell bodies contact each other and rest on the basement membrane that underlies the sensory epithelium ( Figures 47.3d and 47.4b,c ). Rod-like phalangeal processes extend from the cell body, interdigitating between the hair cells, to the luminal surface where they expand to fill the spaces between hair cells ( Figures 47.3d,e,f and 47.4d,e,f ). Supporting cells possess a fairly extensive cytoskeletal system that is particularly well developed in the cells of the organ of Corti. These phalanges contain bundles of microtubules, which can act like scaffolding poles/suspension struts to provide structural support (described in more detail later). At the apical, luminal poles, there are cytoskeletal assemblies that contain actin arranged in filamentous bundles running parallel to the luminal surface of the cell, anchoring to an adherens-like region within the intercellular junction that joins it to the adjacent hair cell ( Figure 47.3e ). Actin bands that run circumferentially around the neck or cortex of an epithelial cell are present in all epithelial cells and are thought to provide structural support at the points of adhesion between adjacent cells. These cortical actin bands are unusually wide in sensory epithelia of the inner ear ( Figure 47.3e ), indicating the importance of rigidity at the apical surface of these tissues. Supporting cells are functionally coupled to each other by substantial numbers of large gap junctions ( Figures 47.6e and 47.7o ). , – Gap junctions are sites of direct cytoplasmic communication between adjacent cells where clusters of pore-forming channel proteins in the membrane of one cell are in direct register with clusters of pore-forming channel proteins in the membrane of its neighbour. When these clusters of proteins dock together, they can form continuous aqueous pores that connect the cytoplasm of the adjacent cells. The protein subunits that form gap junction channels are members of the connexin protein family. At least 20 different types, or isoforms, of connexin have been identified. Six connexins form a hemi-channel or connexon, and the connexons of two adjacent cells align symmetrically to form the communication pathway between the cells. Gap junction channels are clustered in the plane of the membrane to form ‘plaques’ that can contain up to several thousand connexons. The channels allow the passage of small metabolites (up to 1.2 kDa in size), ions and second messengers, coupling the cells both electrically and chemically. Numerous gap junctions are present at points of contact between adjacent supporting cell bodies and between the head regions of adjacent cells, but there are no gap junctions associated with hair cells. , The large size and number of gap junction plaques between all supporting cells mean that the supporting cell population can be regarded as a functional syncytium, from which hair cells are functionally isolated. , In all vertebrate classes from fish to mammals, gap junction plaques in inner ear sensory tissues are typically enormous, among the largest in the whole body, covering several square micrometres (µm ) in area and containing several thousand channels. One suspected role for supporting cells is thought to be the removal of excess K+ ions from the intercellular spaces of the sensory epithelium during hair cell repolarization events. Such a mechanism could thereby maintain the low K+ environment around the body of the hair cell necessary for transduction and sensitivity to stimulation. It has been proposed that the gap junctions provide a means to ferry the K+ away, preventing local accumulation.
Electrical properties and cardiac myocyte structure
Burt B. Hamrell in Cardiovascular Physiology, 2018
Cardiac muscle is partially composed of a highly branched network of small, 12 × 100 micron (μm) myocytes (Figure 5.1). There are several interchangeable names for a cardiac muscle cell: myocardial or cardiac muscle fiber and myocardial or cardiac myocyte. Each myocyte is bounded longitudinally by intercalated discs and can branch (Figure 5.1). The intercalated discs connect myocytes end-to-end (Figure 5.1). Finger-like projections of the sarcolemma at the ends of myocytes are interlocked to form the intercalated disc. Desmosomes are dense areas of adherence within the intercalated disc (Figure 5.1). Desmosomes mechanically link myocytes and transmit force from one myocyte to the next. Of great importance are other specialized dense areas within the intercalated disc, the gap junctions (Figure 5.1), which have low electrical resistance (Figure 5.1). The gap junctions contain channel-like structures called connexins that are low resistance pathways from the end of one myocyte to the next interconnected myocyte. Ions move relatively freely from myocyte to myocyte through gap junctions. This accounts for the low myocyte-to-myocyte resistance and high conductance throughout heart muscle tissue.
Keratitis–Ichthyosis–Deafness Syndrome
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Connexins (Cx) are a family of 21 structurally related transmembrane proteins (subunits) that contain four transmembrane domains (TM1-TM4) linked by two extracellular loops (ECL) and one intracellular loop (ICL), with the amino terminus (NT) and the carboxyl terminus (CT) located inside the cytoplasm. Posttranslational modification through phosphorylation on serines enables connexins to travel to membranes, assemble, degrade, and gate functional gap junction channels (GJC). Based on their molecular masses (ranging from 25 to 62 kDa), connexins are designated as connecxin26 (Cx26), connecxin30 (Cx30), connecxin32 (Cx32), connecxin43 (Cx43), connecxin46 (Cx46), connecxin50 (Cx50), etc. Further, according to sequence similarities at the nucleotide and amino acid levels, connexins are separated into three categories α, β, or γ. While most cell types express >1 connexin (e.g., keratinocytes make nine connexins, including Cx26, Cx30, Cx31, and Cx43), one connexin protein type may be produced by the cells of different tissues (e.g., Cx26, Cx30, Cx31, and Cx43 are secreted by the epithelia of the inner ear, cornea, and the epidermis and its appendages) [2,3]. With a short half-life of 2–4 h, connexins participate in intracellular connexin−protein interaction, cell−extracellular space exchange, and cell−cell communication through formation of hemichannels and GJC Specifically, six connexin subunits gather together as hemichannel (or gap junction hemichannel, also known as connexon) in the endoplasmic reticulum or Golgi body and then move to cellular membranes, where two hemichannels join through hydrophobic interactions to form GJC, which is an aqueous pore between the cytoplasm of two adjacent cells, facilitating the exchange of ions (K+, Ca2+), signaling molecules (IP3, cAMP, cGMP, ATP) and metabolites (e.g., glucose, sugar, amino acid, glutathione) (Figure 42.1). Via these activities, connexins activate signaling pathways and affect cellular phenotypes. Not surprisingly, total or partial connexin dysfunctions may lead to a variety of genetic disorders such as skin abnormalities, cardiopathies, neurodegenerative and developmental diseases, cataracts, hereditary deafness, and cancer (collectively known as connexinopathies) (Table 42.1) [4–6].
Correlation of Expression of Connexin mRNA Isoforms with Degree of Cellular Differentiation
Published in Cell Adhesion and Communication, 1996
Elizabeth Rosenberg, Ronald A. Faris, David C. Spray, Barbara Monfils, Sergio Abreu, Isidore Danishefsky, Lola M. Reid
Examination of rat hepatic cell lines has revealed a correlation between the differentiated state of the cells and the gap junctional proteins, or connexins, they express. The cell lines RLC (Gershenson et al, 1970) and FTO.2B (Killary et al, 1984) were examined and compared to primary adult hepatocytes for expression of fetal and adult hepatic antigens under various tissue culture conditions. Maximal expression of fetal antigens was observed in cells grown in serum-supplemented medium, on either tissue culture plastic or type IV collagen. Maximal expression of adult specific antigens was seen in cells grown in a hormonally defined medium containing heparin, on type I or type IV collagen. The cell line RLC strongly expressed fetal antigens, while FTO.2B expressed both fetal and adult antigens. These cell lines and another poorly differentiated hepatic cell line, WB-F344 (Tsao et al., 1984) were used to assess the developmental profile of mRNAs encoding isoforms of gap junctions: connexins 26, 32, and 43. The cell lines each transcribed mRNAs of all three connexins, as determined by transcriptional elongation analysis. By contrast, only certain of the connexin mRNAs could be detected in specific cell lines by Northern analysis: RLC expressed only connexin 43 mRNA; WB-F344 expressed connexin 26 and 43 mRNAs; and FTO.2B, the most differentiated cell line, expressed connexin 32 and 43 mRNAs. Selection among the connexin mRNAs appears to occur post-transcriptionally. Culture of the cell lines in hormonally defined medium vs. serum supplemented medium did not affect the patterns of connexin mRNA abundance. When the cell lines were cultured in hormonally defined medium containing heparin, however, the level of connexin mRNAs did vary: Connexin 26 mRNA increased in WB-F344 cells, and connexins 32 and 43 mRNAs increased in FTO.2B, but connexin 43 mRNA decreased in WB-F344 and RLC. The abundance of connexin mRNAs also varied when the cell lines were analyzed at different cell densities: connexin 43 mRNA increased with cell density in RLC and WB-F344, and connexin 26 mRNA peaked at an intermediate density and fell at higher cell densities in WB-F344. The differences in connexin mRNA expression among cell lines characteristic of different stages of hepatic differentiation, and the differences in regulation of connexin mRNAs in the hepatic cell lines, suggest distinct biological roles of the highly homologous proteins. Moreover, connexin gene expression may be a marker of hepatic development: as hepatocytes differentiate the proportions of connexin 43 then 26 mRNAs decrease while that of connexin 32 mRNA increases.
Connexin Genes in the Mouse and Human Genome
Published in Cell Communication & Adhesion, 2001
JÜRgen Eiberger, Joachim Degen, Alessandro Romualdi, Urban Deutsch, Klaus Willecke, Goran Söhl
Gap junctions serve for direct intercellular communication by docking of two hemichannels in adjacent cells thereby forming conduits between the cytoplasmic compartments of adjacent cells. Connexin genes code for subunit proteins of gap junction channels and are members of large gene families in mammals. So far, 17 connexin (Cx) genes have been described and characterized in the murine genome. For most of them, orthologues in the human genome have been found (see White and Paul 1999; Manthey et al. 1999; Teubner et al. 2001; Söhl et al. 2001). We have recently performed searches for connexin genes in murine and human gene libraries available at EMBL/Heidelberg, NCBI and the Celera company that have increased the number of identified connexins to 19 in mouse and 20 in humans. For one mouse connexin gene and two human connexin genes we did not find orthologues in the other genome. Here we present a short overview on distinct connexin genes which we found in the mouse and human genome and which may include all members of this gene family, if no further connexin gene will be discovered in the remaining non-sequenced parts (about 1-5%) of the genomes.
Connexin Channels, Connexin Mimetic Peptides and ATP Release
Published in Cell Communication & Adhesion, 2003
Luc Leybaert, Katleen Braet, Wouter Vandamme, Liesbet Cabooter, Patricia E. M. Martin, W. Howard Evans
Connexin hemichannels, that is, half gap junction channels (not connecting cells), have been implicated in the release of various messengers such as ATP and glutamate. We used connexin mimetic peptides, which are, small peptides mimicking a sequence on the connexin subunit, to investigate hemichannel functioning in endothelial cell lines. Short exposure (30 min) to synthetic peptides mimicking a sequence on the first or second extracellular loop of the connexin subunit strongly supressed ATP release and dye uptake triggered by either intracellular InsP3elevation or exposure to zero extracellular calcium, while gap junctional coupling was not affected under these conditions. The effect was dependent on the expression of connexin-43 in the cells. Connexin mimetic peptides thus appear to be interesting tools to distinguish connexin hemichannel from gap junction channel functioning. In addition, they are well suited to further explore the role of connexins in cellular release or uptake processes, to investigate hemichannel gating and to reveal new unknown functions of the large conductance hemichannel pathway between the cell and its environment. Work performed up to now with these peptides should be re-interpreted in terms of these new findings.
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