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PubMed1986

Altered regulation of airway epithelial cell chloride channels in cystic fibrosis.

In many epithelial cells the chloride conductance of the apical membrane increases during the stimulation of electrolyte secretion. Single-channel recordings from human airway epithelial cells showed that beta-adrenergic stimulation evoked apical membrane chloride channel activity, but this response was absent in cells from patients with cystic fibrosis (CF). However, when membrane patches were excised from CF cells into media containing sufficient free calcium (approximately 180 nanomolar), chloride channels were activated. The chloride channels of CF cells were similar to those of normal cells as judged by their current-voltage relations, ion selectivity, and kinetic behavior. These findings demonstrate the presence of chloride channels in the apical membranes of CF airway cells. Their regulation by calcium appears to be intact, but cyclic adenosine monophosphate (cAMP)-dependent control of their activity is defective.

Calcium↗
PubMed2000

Functional consequences of chloride channel gene (CLCN1) mutations causing myotonia congenita.

OBJECTIVE: To determine the functional consequences of missense mutations within the skeletal muscle chloride channel gene CLCN1 that cause myotonia congenita. BACKGROUND: Myotonia congenita is a genetic muscle disease associated with abnormalities in the skeletal muscle voltage-gated chloride (ClC-1) channel. In order to understand the molecular basis of this inherited disease, it is important to determine the physiologic consequences of mutations found in patients affected by it. METHODS: The authors used a mammalian cell (human embryonic kidney 293) expression system and the whole-cell voltage-clamp technique to functionally express and physiologically characterize five CLCN1 mutations. RESULTS: The I329T mutation shifted the voltage dependence of open probability of ClC-1 channels to the right by 192 mV, and the R338Q mutation shifted it to the right by 38 mV. In addition, the I329T ClC-1 channels deactivated to a lesser extent than normal at negative potentials. The V165G, F167L, and F413C ClC-1 channels also shifted the voltage dependence of open probability, but only by +14 to +20 mV. CONCLUSIONS: The functional consequences of these mutations form the physiologic argument that these are disease-causing mutations and could lead to myotonia congenita by impairing the ability of the skeletal muscle voltage-gated chloride channels to maintain normal muscle excitability. Understanding of genetic and physiologic defects may ultimately lead to better diagnosis and treatment of patients with myotonia congenita.

Chloride Channels↗
PubMed2006

The ABC protein turned chloride channel whose failure causes cystic fibrosis.

CFTR chloride channels are encoded by the gene mutated in patients with cystic fibrosis. These channels belong to the superfamily of ABC transporter ATPases. ATP-driven conformational changes, which in other ABC proteins fuel uphill substrate transport across cellular membranes, in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient. New structural and biochemical information from prokaryotic ABC proteins and functional information from CFTR channels has led to a unifying mechanism explaining those ATP-driven conformational changes.

ATP-Binding Cassette Transporters↗
PubMed1999

Structure and function of the CFTR chloride channel.

Structure and Function of the CFTR Chloride Channel. Physiol. Rev. 79, Suppl.: S23-S45, 1999. - The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl- channel. It is located predominantly in the apical membrane of epithelia where it mediates transepithelial salt and liquid movement. Dysfunction of CFTR causes the genetic disease cystic fibrosis. The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. Here we review the structure and function of this unique channel, with a focus on how the various domains contribute to channel function. The MSDs form the channel pore, phosphorylation of the R domain determines channel activity, and ATP hydrolysis by the NBDs controls channel gating. Current knowledge of CFTR structure and function may help us understand better its mechanism of action, its role in electrolyte transport, its dysfunction in cystic fibrosis, and its relationship to other ABC transporters.

ATP-Binding Cassette Transporters↗
PubMed2004

CLIC-5A functions as a chloride channel in vitro and associates with the cortical actin cytoskeleton in vitro and in vivo.

CLIC-5A is a member of the chloride intracellular channel protein family, which is comprised of six related human genes encoding putative chloride channels. In this study, we found that reconstitution of purified recombinant CLIC-5A into artificial liposomes resulted in a dose-dependent chloride efflux that was sensitive to the chloride channel blocker IAA-94. CLIC-5A was originally isolated as a component of an ezrin-containing cytoskeletal complex from human placental microvilli. Here we show that similar protein complexes can be isolated using either immobilized CLIC-5A or the C-terminal F-actin-binding domain of ezrin and that actin polymerization is required for de novo assembly of these complexes. To investigate the behavior of CLIC-5A in vivo, JEG-3 placental choriocarcinoma cells were stably transfected with epitope-tagged CLIC-5A. In fixed cells, CLIC-5A displayed a polarized distribution and colocalized with ezrin in apical microvilli. Microvillar localization of CLIC-5A was retained after Triton X-100 extraction and was disrupted by treatment with latrunculin B. In transient transfections assays, we mapped a region between residues 20 and 54 of CLIC-5A that is required for targeting of CLIC-5A to microvilli in JEG-3 cells. Interestingly, expression of CLIC-5A in JEG-3 cells did not enhance the rate of iodide efflux in intact cells, suggesting that if CLIC-5A is a chloride channel, its channel activity may be restricted to intracellular membrane compartments in these cells. Regardless of its role in ion transport, CLIC-5A, like ezrin, may play an important role in the assembly or maintenance of F-actin-based structures at the cell cortex.

Actins↗
PubMed2003

Effects of chloride channel blockers on hypotonicity-induced contractions of the rat trachea.

1. We have investigated the inhibitory effects of blockers of volume-activated (Cl(vol)) and calcium-activated (Cl(Ca)) chloride channels on hypotonic solution (HS)-induced contractions of rat trachea, comparing their effects with those of the voltage-dependent calcium channel (VDCC) blocker nifedpine. 2. HS elicited large, stable contractions that were partially dependent on the cellular chloride gradient; a reduction to 41.45+/-7.71% of the control response was obtained when extracellular chloride was removed. In addition, HS-induced responses were reduced to 26.8+/-5.6% of the control by 1 microm nifedipine, and abolished under calcium-free conditions, indicating a substantial requirement for extracellular calcium entry, principally via VDCCs. 3. The established Cl(vol) blockers tamoxifen (</=10 microm) and 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (1-100 microm), at concentrations previously reported to inhibit Cl(vol) in smooth muscle, did not significantly inhibit HS-induced contractions. 4. In contrast, the recognized Cl(Ca) blocker niflumic acid (NFA; 1-100 microm) produced a reversible, concentration-dependent inhibition of HS responses, with a reduction to 36.6+/-6.4% of control contractions at the highest concentration. The mixed Cl(vol) and Cl(Ca) blocker, 5-nitro 2-(3-phenylpropylamine) benzoic acid (NPPB; 10-100 microm) also elicited concentration-related inhibition of HS-induced contractions, producing a decrease to 35.9+/-11.3% of the control at 100 microm. 5. Our results show that HS induces reversible, chloride-dependent contractions of rat isolated trachea that were inhibited by NFA and NPPB, while exhibiting little sensitivity to recognized blockers of Cl(vol). The data support the possibility that opening of calcium-activated chloride channels under hypotonic conditions in respiratory smooth muscle may ultimately lead to VDCC-mediated calcium entry and contraction.

Animals↗
PubMed1991

Antagonists of epithelial chloride channels inhibit cAMP synthesis.

In past studies we observed that the chloride channel blocker, diphenylamine-2-carboxylate (DPC) and chemically related drugs (Hoechst compounds 131, 143, 144) inhibited cAMP formation in mouse pituitary tumor cells. The object of this study was to determine whether these drugs inhibited chloride transport in human T-84 colonic carcinoma cells through an effect on cAMP metabolism. Chloride secretion (measured as 125I efflux from isotope-preloaded cells) was stimulated in a concentration-dependent manner by vasoactive intestinal polypeptide (VIP) (EC50 = 1.5 x 10(-10) M) which similarly increased cAMP synthesis (EC50 = 1.6 x 10(-8) M). The cAMP response to VIP was inhibited 17, 52, 55, and 78% maximally by DPC and compounds 144, 143, and 131, respectively. In untreated T-84 cells, 125I secretion fell by 66% after 3 min; VIP (10(-7) M) increased secretion about fivefold over the same period. Both basal and VIP-stimulated 125I secretion were inhibited up to 60% by compound 131. Pretreatment of cells with pertussis toxin did not attenuate the inhibitory effect of channel blockers on either VIP-stimulated cAMP synthesis or 125I secretion. The cationophore, A-23187, which had no effect on cAMP formation, and 8-Br-cAMP both stimulated 125I secretion from T-84 cells. These secretory responses were inhibited by compound 131. The mechanism by which phenylanthranilic acids antagonize cAMP synthesis and its significance is not known; however, the data suggest that this family of drugs may inhibit chloride transport by both cAMP-dependent and independent mechanisms.

Chloride Channels↗
PubMed1998

Relevance of the D13 region to the function of the skeletal muscle chloride channel, ClC-1.

Although hydropathy analysis of the skeletal muscle chloride channel protein, ClC-1, initially predicted 13 potential membrane spanning domains (D1 to D13), later topological studies have suggested that domain D4 is extracellular and that D13, conserved in all eukaryotic ClC channels, is located within the extensive cytoplasmic tail that makes up the carboxyl terminus of the protein. We have examined the effect of deleting D13 (DeltaD13) and the function of the carboxyl tail by removing the final 72 (fs923X), 100 (fs895X), 125 (L869X), 398 (N596X), and 420 (Q574X) amino acids from rat ClC-1. Appropriate cDNA constructs were prepared and expressed using the baculovirus Sf9 insect cell system. Patch clamp analysis of chloride currents in Sf9 cells showed that only relatively insubstantial changes could be attributed to the expressed fs923X, fs895X, and DeltaD13 mutants compared with wild type rat ClC-1. For N596X and Q574X, however, adequate mRNA could be detected, but neither patch clamp nor polyacrylamide gel electrophoresis showed corresponding protein production. By contrast, expression of L869X was demonstrable by polyacrylamide gel electrophoresis, but no chloride conductance attributable to it could be detected. Overall, our results indicate that the domain D13 is dispensable, as are the final 100 amino acids, but not the final 125 amino acids or more, of the carboxyl tail. Some essential region of unknown significance, therefore, appears to reside in the 18 amino acids after D13, from Lys877 to Arg894.

Amino Acid Sequence↗
PubMed1996

Volume regulation in the bovine lens and cataract. The involvement of chloride channels.

The purpose of this study was to investigate volume regulation in the lens and its involvement in lens opacification (cataract) and the role of chloride channels in these processes. Single, isolated lens fiber cells from the lens were whole cell patch clamped. When exposed to hypotonic solution, and outwardly rectifying whole-cell current was activated. The current increased from 1.0 to 32.6 pA/pF, reversed at the chloride reversal potential (Ec1 = O mV), and was blocked by the chloride channel blockers 5, nitro-2-(3-phenylpropylamino) benzoate (NPPB) and tamoxifen. Replacing all but 5mM of the external chloride with gluconate caused the reversal potential to shift +33 mV, consistent with a CL- current with a gluconate/chloride permeability ratio of 0.26. When the whole lens of the eye was exposed to hypotonic solution, there was an initial increase in anterior-posterior diameter (5-8 min), representing lens swelling of 6.5%. This was followed by a decrease in volume to a new steady state value that lasted for up to 2 h. In the longer term (> or = 2h), the lenses began to swell again. The simultaneous exposure to hypotonic solution and tamoxifen or NPPB caused swelling and prevented this volume regulation. Lenses incubated in hypotonic solution and hypotonic solution containing tamoxifen becane ipaque after a 2-h incubation period. We conclude that the lens is able to volume regulate. It possesses volume-activated Cl- channels, the inhibition of which results in inhibition of volume regulation, lens swelling and opacification. Our data suggest the long-term prophylactic use of tamoxifen may make the patient more susceptible to cataract.

Animals↗
PubMed2006

Intracellular localization of ClC chloride channels and their ability to form hetero-oligomers.

ClC chloride channels (ClCs) can be classified into two groups in terms of their cellular localizations: ClCs present in the plasma membranes and those residing in intracellular organelles. Members of the latter group, including ClC-3, ClC-4, ClC-5, ClC-6, and ClC-7, are often co-expressed in a variety of cell types in many organs. Although the localization of individual channels within cells has been investigated, the degree of overlap between the locations of different ClCs in the same cell has not been clarified. To address this question, different combinations of ClCs, engineered to encode specific epitope tags (FLAG or HA), were either transiently or stably transfected into HEK293 cells, and we then compared the intracellular localization of the expressed channel proteins by immunofluorescence microscopy. Immunofluorescence images of the alternatively labeled channels clearly showed significant co-localization between all pair-wise combinations of ClCs. In particular, ClC-3, ClC-4, and ClC-5 showed a high degree of co-localization. As a significant degree of co-localization between ClCs was observed, we used co-immunoprecipitation to evaluate oligomer formation, and found that each ClC tested could form homo-oligomers, and that any pair-wise combination of ClC-3, ClC-4, and ClC-5 could also form hetero-oligomers. Neither ClC-6 nor ClC-7 was co-precipitated with any other channel protein. These results suggest that within cells ClC-3, ClC-4, and ClC-5 may have combinatorial functions, whereas ClC-6 and ClC-7 are more likely to function as homo-oligomers.

Biomarkers↗
PubMed1988

Phosphorylation-activated chloride channels in human skin fibroblasts.

A chloride-selective channel has been found using patch-clamp electrophysiology in human skin fibroblasts and it exhibits many of the biophysical properties of the Cl- channel found in airway epithelia. As in the case of epithelial Cl- channels, Cl- channels in fibroblasts are activated at depolarized membrane potentials in excised patches, rectifying in an outward direction with a unit conductance of 33 pS at 0 mV. Furthermore, the agonists forskolin and prostaglandin E2 evoke Cl- channel activity in cell-attached patches. The effect of these agonists can be mimicked by direct application of catalytic subunit of protein kinase A with ATP and Mg2+ to the internal membrane surface of excised, inside-out patches. The Cl- channel is also sensitive to inhibition by the stilbene derivative, DIDS. These results indicate that fibroblasts may provide a convenient and available model for the study of epithelial Cl- channel regulation and accelerate efforts to determine the regulatory defect expressed in cystic fibrosis.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMedDate not supplied

Chloride channel blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid and anthracene-9-carboxylic acid inhibit contractions of pregnant rat myometrium in vitro.

OBJECTIVE: We compared in vitro relaxant effect of chloride channel modulators, such as 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and anthracene-9-carboxylate (9-AC), and beta(2)-adrenergic agonists, such as ritodrine, in pregnant rat myometrium. METHODS: Isolated myometrial strips were obtained from eight pregnant rats, and the strips were mounted in organ baths for recording isometric tension. The effects of 10(-8)-10(-4) M ritodrine, 10(-6)-3 x 10(-4) M NPPB, and 10(-6)-10(-3) M 9-AC on spontaneous contractions were recorded. RESULTS: Ritodrine (10(-8)-10(-5) M) completely inhibited the amplitude and frequency of spontaneous contractions in myometrial strips isolated from pregnant rats in a concentration-dependent manner, but the relaxant effect of ritodrine at 10(-4) M concentration resulted in tachyphylaxis. The chloride channel blocker NPPB (10(-6)-3 x 10(-4) M) and the chloride transport inhibitor 9-AC (10(-5)-10(-3) M) decreased the amplitude of spontaneous myometrial contractions in a concentration-dependent manner; the maximum inhibition produced by the highest tested concentration of each drug was 43.8% and 42.1% of the original degree of spontaneous contractions, respectively. The frequency of myometrial contractions was significantly inhibited by NPPB and 9-AC beginning with the concentration of 10(-4) M. CONCLUSION: NPPB and 9-AC appear to be effective relaxants of pregnant rat myometrium. These effects of NPPB and 9-AC might be therapeutically advantageous in clinical management of preterm labor.

Adrenergic beta-Agonists↗
PubMed2005

Identification and functional characterization of a voltage-gated chloride channel and its novel splice variant in taste bud cells.

Taste bud cells are epithelial cells with neuronal properties. Voltage-dependent ion channels have been physiologically described in these cells. Here, we report the molecular identification and functional characterization of a voltage-gated chloride channel (ClC-4) and its novel splice variant (ClC-4A) from taste bud cells. ClC-4A skipped an exon near its 5'-end, incurring the loss of 60 amino acids at the N terminus. In situ hybridization and immunohistochemistry localized these two channels' transcripts and proteins to a subset of taste bud cells. Electrophysiological recordings of the heterologously expressed channels in Xenopus oocytes showed that ClC-4 and ClC-4A have opposite sensitivity to pH and unique ion selectivity. The chloride channel blockers niflumic acid and 5-nitro-2-(3-phenylpropylamino)benzoic acid had a slight or no inhibitory effect on the conductance of ClC-4, but both blockers inhibited ClC-4A, suggesting that ClC-4A is a candidate channel for an acid-induced 5-nitro-2-(3-phenylpropylamino)benzoic acid-sensitive current. Furthermore, these two channels may play a role in bitter-, sweet-, and umami-mediated taste transmission by regulating transmitter uptake into synaptic vesicles.

Alternative Splicing↗
PubMed1998

Molecular and functional characterization of a calcium-sensitive chloride channel from mouse lung.

A protein (mCLCA1) has been cloned from a mouse lung cDNA library that bears strong sequence homology with the recently described bovine tracheal, Ca2+-sensitive chloride channel protein (bCLCA1), bovine lung endothelial cell adhesion molecule-1 (Lu-ECAM-1), and the human intestinal Ca2+-sensitive chloride channel protein (hCLCA1). In vitro, its 3.1-kilobase message translates into a 100-kDa protein that can be glycosylated to an approximately 125-kDa product. SDS-polyacrylamide gel electrophoresis from lysates of mCLCA1 cDNA-transfected transformed human embryonic kidney cells (HEK293) reveals proteins of 130, 125, and 90 kDa as well as a protein triplet in the 32-38 kDa size range. Western analyses with antisera raised against Lu-ECAM-1 peptides show that the N-terminal region of the predicted open reading frame is present only in the larger size proteins (i.e. 130, 125, and 90 kDa), whereas the C-terminal region of the open reading frame is observed in the 32-38 kDa size proteins, suggesting a posttranslational, proteolytic processing of a precursor protein (125/130 kDa) into 90 kDa and 32-38 kDa components similar to that reported for Lu-ECAM-1. Hydrophobicity analyses predict four transmembrane domains for the 90-kDa protein. The mCLCA1 mRNA is readily detected by Northern analysis and by in situ hybridization in the respiratory epithelia of trachea and bronchi. Transient expression of mCLCA1 in HEK293 cells was associated with an increase in whole cell Cl- current that could be activated by Ca2+ and ionomycin and inhibited by 4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid, dithiothreitol, and niflumic acid. The discovery of mCLCA1 opens the door for further investigating the possible contribution of a Ca2+-sensitive chloride conductance to the pathogenesis of cystic fibrosis.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1989

Vasoconstrictor hormones depolarize renal glomerular mesangial cells by activating chloride channels.

Mesangial cells are smooth muscle-like cells of the renal glomerulus which contract and produce prostaglandins in response to vasopressin and angiotensin. These responses serve to regulate the glomerular capillary filtering surface area. We have used the membrane potential-sensitive fluorescent dye bis-oxonol and the intracellular fluorescent calcium-sensitive probe Indo-1 to study the changes in membrane potential (Em) and intracellular free calcium concentration ([Ca2+]i) in cultured rat mesangial cells in response to vasoconstrictor hormones. Basal [Ca2+]i was 227 +/- 4 nM, and stimulation by maximal concentrations of either vasopressin or angiotensin resulted in a transient 4-6-fold rise. Resting membrane potential was 45.8 +/- 0.9 mV and vasoconstrictor hormones caused a depolarization of 14-18 mV. The following extracellular ion substitutions indicated that chloride efflux was the predominant ion flux responsible for depolarization: 1) depolarization persisted when sodium in the medium was substituted with N-methylglucamine; 2) substitution of medium sodium chloride with sodium gluconate, which enhances the gradient for chloride efflux, augmented vasoconstrictor-stimulated depolarization; 3) suspension of cells in potassium chloride medium resulted in depolarization, following which, stimulation by either vasopressin or angiotensin resulted in hyperpolarization; and 4) this hyperpolarization did not occur when potassium gluconate medium was used to depolarize the cells. The calcium ionophore ionomycin also resulted in membrane depolarization. However, prevention of the rise in [Ca2+]i by prior exposure to ionomycin in calcium-free medium or by loading mesangial cells with the intracellular calcium buffer BAPTA did not abrogate the depolarization response to vasoconstrictor hormones. This indicates that a rise in intracellular calcium is not necessary for depolarization. In contrast, prior depolarization of the cells using varying concentrations of KCl in the external medium, which dissipated the electrochemical gradient for chloride efflux, resulted in a corresponding prolongation of the transient calcium response to vasopressin and angiotensin. These findings indicate that angiotensin and vasopressin depolarize mesangial cells by activating chloride channels and that this activation can occur by both calcium-dependent and -independent mechanisms. In addition, activation of chloride channels with resulting depolarization may serve to modulate the calcium signal.

Angiotensin II↗
PubMed2000

MOD-1 is a serotonin-gated chloride channel that modulates locomotory behaviour in C. elegans.

The neurotransmitter and neuromodulator serotonin (5-HT) functions by binding either to metabotropic G-protein-coupled receptors (for example, 5-HT1, 5-HT2, 5-HT4 to 5-HT7), which mediate 'slow' modulatory responses through numerous second messenger pathways, or to the ionotropic 5-HT3 receptor, a non-selective cation channel that mediates 'fast' membrane depolarizations. Here we report that the gene mod-1 (for modulation of locomotion defective) from the nematode Caenorhabditis elegans encodes a new type of ionotropic 5-HT receptor, a 5-HT-gated chloride channel. The predicted MOD-1 protein is similar to members of the nicotinic acetylcholine receptor family of ligand-gated ion channels, in particular to GABA (gamma-aminobutyric acid)- and glycine-gated chloride channels. The MOD-1 channel has distinctive ion selectivity and pharmacological properties. The reversal potential of the MOD-1 channel is dependent on the concentration of chloride ions but not of cations. The MOD-1 channel is not blocked by calcium ions or 5-HT3a-specific antagonists but is inhibited by the metabotropic 5-HT receptor antagonists mianserin and methiothepin. mod-1 mutant animals are defective in a 5-HT-mediated experience-dependent behaviour and are resistant to exogenous 5-HT, confirming that MOD-1 functions as a 5-HT receptor in vivo.

Alleles↗
PubMed1994

The substituted benzimidazolone NS004 is an opener of the cystic fibrosis chloride channel.

Cystic fibrosis is a major inherited disorder involving abnormalities of fluid and electrolyte transport in a number of different organs. Epithelial cells of cystic fibrosis patients have a decreased capacity to secrete chloride in response to cAMP-mobilizing agents because of the mutation of a single gene. The gene product, the cystic fibrosis transmembrane conductance regulator or CFTR, is a chloride channel. The most frequent mutation is a deletion of phenylalanine in position 508 (delta F508-CFTR) that reduces both the expression of the CFTR protein at the cell surface, and the activity of the Cl- channel. This work presents the properties of NS004, a substituted benzimidazolone, which is the first activator of normal and mutant CFTR-associated chloride channels to be described. NS004 activated CFTR and delta F508-CFTR Cl- channels expressed in Xenopus oocytes, and increased 125I efflux (via the Cl- channel) from Vero cells expressing CFTR and delta F508-CFTR. Application of NS004 to the external side of outside-out patches excised from these CFTR- and delta F508-CFTR-expressing cells induced a marked and reversible increase in channel activity.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Complete genomic structure of the CLCN6 and CLCN7 putative chloride channel genes(1).

The CLC family of voltage-gated chloride channels comprises nine members in mammals. CLCN6 and CLCN7 belong to a novel, poorly characterized subbranch of this family. We investigated the genomic organization of the human CLCN6 gene, as well as the murine CLCN6 and CLCN7 genes. The human and murine CLCN6 genes both consist of 23 exons and share a nearly identical genomic structure. The coding region of mouse CLCN7 is composed of 25 exons. Comparison of the genomic organization of CLCN6 and CLCN7 genes shows that just eight introns are located at corresponding cDNA positions. Moreover, no significant gene structure homology to other members of the CLC family could be detected indicating a great structural diversity of mammalian CLC genes.

Amino Acid Sequence↗