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Physiology 20: 398-407, 2005; doi:10.1152/physiol.00033.2005
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Physiology, Vol. 20, No. 6, 398-407, December 2005
© 2005 Int. Union Physiol. Sci./Am. Physiol. Soc.

REVIEW

Ubiquitylation of Ion Channels

Hugues Abriel1,2 and Olivier Staub1

1 Department of Pharmacology and Toxicology and
2 Service of Cardiology, University of Lausanne, Switzerland

Hugues.Abriel{at}unil.ch Olivier.Staub{at}unil.ch


   Abstract
 
Ubiquitylation (i.e., covalent attachment of ubiquitin moieties to proteins) of ion channels allows regulation of their activity and fate. Nedd4/Nedd4-like ubiquitin-protein ligases bind to, ubiquitylate, and modulate the internalization of several channels bearing PY motifs, whereas endoplasmic reticulum-associated degradation (involving ubiquitylation) plays an important role in the biogenesis of normal and defective channels.


   Introduction
Top
 Introduction
Ubiquitylation of Ion Channels...
 Ubiquitylation of Ion Channels...
 ERAD-Mediated Ubiquitylation of...
 ERAD-Mediated Ubiquitylation of...
 Ubiquitylated Ion Channels:...
 Conclusions and Perspectives
 References
 
Ion channels are expressed ubiquitously in animal cells and are involved in many essential homeostatic functions, such as membrane and transcellular transport of electrolytes, cellular excitability, cell growth, and apoptosis. Furthermore, regulation of ion-channel activity is known to be important for numerous physiological processes, such as morphogenesis and organogenesis, homeostasis of body electrolytes, and cellular immune response, to mention a few examples. Supporting these crucial roles of ion channels, many human genetic diseases have been shown to be caused by altered function and regulation of ion channels (5). Diseases of this class have been called genetic "channelopathies" (47). The aim of this review is to summarize recent findings demonstrating that ion channels can be regulated via their ubiquitylation (covalent attachment of ubiquitin polypeptides, also referred to as ubiquitination or ubiquitinylation). Note that for the sake of conciseness, only ion channels for which there is direct biochemical evidence of ubiquitylation will be discussed.

During the past decade, as with many other proteins, ion-channel subunits have been found to be ubiquitylated (Table 1Go). Ubiquitin is a 76-amino acid protein expressed in all animal and plant cells. It belongs to a family of structurally similar proteins fulfilling related functions [ubiquitin-like proteins such as small ubiquitin-related modifier (SUMO), neuronal precursor cell developmentally downregulated (Nedd) 8, or interferon stimulated gene-15 (68)]. Covalent attachment of ubiquitin to proteins is a posttranslational modification that was originally shown to tag cytosolic proteins for rapid degradation by the proteasome. In contrast, membrane proteins are labeled for internalization and/or degradation by the lysosome or the proteasome (57). Ubiquitylation involves the successive action of a ubiquitin-activating enzyme (called E1; FIGURE 1AGo), a ubiquitin-conjugating or ubiquitin-carrier enzyme (E2), and a ubiquitin-protein ligase (E3). Most of the time, ubiquitin is covalently attached to lysines of the target proteins (FIGURE 1BGo). In addition, ubiquitin itself can also be ubiquitylated, consequently forming polyubiquitin chains, a process that has been proposed to be carried out by E4 enzymes (44). Proteins are either monoubiquitylated (one ubiquitin on one lysine), multiubiquitylated (several monoubiquitylated sites on a protein), or polyubiquitylated (FIGURE 1BGo). There are several lysines on ubiquitin; hence different types of polyubiquitin chains can be formed. Polyubiquitin chains through lysine-48 are usually signals for recognition by the proteasome, whereas monoubiquitin and/or polyubiquitin chains through lysine-63 are used for internalization/endocytosis of numerous membrane proteins (for a review, see Ref. 57) (FIGURE 2Go). Importantly, ubiquitylation is a reversible process, facilitated by deubiquitylating enzymes (DUBs) (4).


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  		Table 1. Ion channels known to be ubiquitylated as of 2005
 


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  		FIGURE 1. Ubiquitin conjugation cascade
A: E1, E2, and E3 are the ubiquitin-activating, -conjugating, and -ligase enzymes, respectively. Ubiquitin (U) is successively carried by these three enzymes. E3s enzymes can specifically recognize the target proteins (here membrane ion channels) and ubiquitylates them. E4 enzymes (not shown here) have been proposed to elongate the polyubiquitin chains. B: ion channels can be either (from left to right) monoubiquitylated, multiubiquitylated, or polyubiquitylated on lysine residues (K).

 


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  		FIGURE 2. Role of ion-channel ubiquitylation
Ubiquitylation of ion channels has been shown to play a role in two major systems of the cell. Note that many aspects of this internalization and degradation process are still under investigation. For example, the role of proteasome-dependent degradation of ion channels is, thus far, mainly speculative.

 

   Ubiquitylation of Ion Channels with a PY Motif
Top
 Introduction
 Ubiquitylation of Ion Channels...
Ubiquitylation of Ion Channels...
 ERAD-Mediated Ubiquitylation of...
 ERAD-Mediated Ubiquitylation of...
 Ubiquitylated Ion Channels:...
 Conclusions and Perspectives
 References
 
ENaC
The best-studied case of an ubiquitylated ion channel is the epithelial sodium channel ENaC. ENaC is expressed in the distal part of the nephron and is involved in sodium homeostasis and blood pressure control by the kidney (41). It is composed of three subunits ({alpha}, ß, {gamma}), each containing two transmembrane domains, one extracellular loop, and short intracellular NH2 and COOH terminals. Of relevance are the so-called PY motifs (P-P-X-Y-X-X-{phi}, where P is a proline, X any amino acid, and {phi} a hydrophobic amino acid) (37) situated at the COOH-terminal regions of each subunit. The physiological importance of ENaC and its PY motifs is underlined by the finding that mutations in the genes encoding ß- and {gamma}-ENaC and inactivating the corresponding PY motifs can cause Liddle’s syndrome, an inherited form of salt-sensitive hypertension (70). Such "Liddle" channels display both higher open probability (21) and elevated cell-surface expression (65, 66, 72), the latter being caused by less-efficient internalization (7). The ENaC PY motifs have been identified as binding sites for ubiquitin-protein ligases of the Nedd4/Nedd4-like family (61, 74), suggesting that ENaC is regulated by ubiquitylation. Indeed, it was shown that ENaC is ubiquitylated on the {alpha}- and {gamma}-subunit (61, 74, 75).

The Nedd4/Nedd4-like protein family comprise nine members in humans (31). They are characterized by a COOH-terminal catalytic homologous to E6-AP-COOH terminus (HECT) domain (30); several WW domains (protein:protein interaction) (76); and an NH2-terminal, calcium-dependent, lipid-binding (C2) domain (56). Although several members of the family have been reported to interact via their WW domains with ENaC (Nedd4, Nedd4-2, WWP1, and WWP2), there is compelling evidence that ENaC is primarily regulated by Nedd4-2:

  1. In Xenopus oocytes and epithelial cells, Nedd4-2 is very efficient in suppressing ENaC activity, whereas Nedd4 has comparably mild effects (2, 35, 36).
  2. Nedd4-2 can be coimmunoprecipitated with ENaC, demonstrating an interaction in cells.
  3. Nedd4-2 is expressed in epithelial cells of the aldosterone-sensitive distal nephron, together with ENaC (22, 32, 35).
  4. In epithelial cells transfected with ENaC, RNA interference experiments suppressing Nedd4-2 increase the transepithelial sodium transport (73).
  5. The Nedd4-2 gene is localized to chromosome 18q21-22 (11), a region linked to a number of blood pressure variants, although a direct linkage with the Nedd4-2 gene has not yet been demonstrated (77).
  6. Nedd4-2 is phosphorylated by the aldosterone-induced Ser/Thr kinase 1 (Sgk1), providing one mode of regulation of ENaC by aldosterone (13, 71).

Finally, it has been suggested that the regulation of ENaC by Nedd4-2 is sensitive to sodium concentration (15, 40).

Voltage-gated Na+ channels
Voltage-gated Na+ channels (Navs) are responsible for the generation of the action potential in most of the excitable cells. Numerous neurological and cardiac diseases are caused by mutations of the genes coding for this family of channels (47). Structurally, they contain a large pore-forming {alpha}-subunit composed of four homologous domains. Each subunit has six {alpha}-helical transmembrane segments and several associated ß-subunits (94). Remarkably, 7 out of the 10 {alpha}-subunits also contain a PY motif in their COOH terminus (23, 62), very similar to ENaC, which raised the possibility that they are also regulated via ubiquitylation by Nedd4/Nedd4-like enzymes. Indeed, in human embryonic kidney 293 cells the cardiac Nav1.5 channel is downregulated in a ubiquitylation-dependent fashion by Nedd4-2 (1, 62, 83). This downregulation depends on the presence of the PY motif, and it involves a decrease of channel numbers at the cell surface (83). It was also demonstrated by yeast two-hybrid and pull-down assays that the COOH terminus of Nav1.5 does interact with cellular Nedd4-2, that Nav1.5 is ubiquitylated in 293 cells and in cardiac tissue, and that Nedd4-2, but not its inactive mutant, enhances ubiquitylation of Nav1.5.

Other Nav {alpha}-subunits may bind to and become regulated by Nedd4/Nedd4-like proteins as well (Nedd4-2, Nedd4, or WWP2) (23, 62). Specifically, it was reported that Nav1.2 and Nav1.3 can be suppressed by Nedd4-2 when coexpressed in 293 cells (23, 62). Other Nav isoforms were also shown to be regulated by Nedd4/Nedd4-like members when coexpressed in Xenopus oocytes (23). These data clearly suggest that all of the Nav channels containing PY motifs can probably be regulated by Nedd4/Nedd4-like enzymes. These studies also indicate that individual channels may be regulated by several Nedd4/Nedd4-like E3 members, and, on the other hand, that an E3 enzyme may be involved in the regulation of different channels. For the moment, we can only speculate on the relevance of these findings. There may be cooperativity of the Nedd4/Nedd4-like enzymes. A possible mechanism may involve a first monoubiquitylation by one enzyme, followed by polyubiquitylation by another one. In this context, it is interesting to mention that Melan A, a membrane protein expressed in melanocytes, is ubiquitylated primarily by Nedd4, whereas its degradation seems to be induced by Itch (another Nedd4/Nedd4-like family member) (51).

ClC-5
ClC-5 is another membrane protein regulated via PY motif-dependent ubiquitylation. Note that recently this ion transporter has been shown to be a chloride/proton exchanger rather than a chloride channel (58, 64). ClC-5 is expressed in endocytically active cells of proximal renal tubules and functions mainly in endocytotic vesicles (34). The gene encoding ClC-5 is mutated in patients with Dent’s disease, which is characterized by urinary loss of low-molecular-weight proteins, calcium, and phosphate and by the formation of kidney stones and appearance of nephrocalcinosis (53). ClC-5 contains in its COOH terminus a motif that resembles PY motifs (i.e., P-L-P-P-Y) that, similarly to the above-described sodium channels, negatively controls cell-surface expression in Xenopus oocytes. Indeed, artificial mutation of the PY motif causes an increase in chloride currents and ClC-5 cell-surface expression (67), which is likely caused by reduced internalization of the mutated channels. Whereas coexpression of wild-type WWP2 (a Nedd4/Nedd4-like family member) has no effect on ClC-5 activity, various mutated forms of WWP2 (containing only WW domains 3 and 4 or either lacking or having mutated HECT domains) increase the ClC-5-dependent chloride currents, suggesting that Nedd4/Nedd4-like family members are regulating ClC-5. In another study (29), it was shown that Nedd4-2 and Nedd4 can interact both in vitro and in vivo in cells with ClC-5 and that Nedd4-2 but not Nedd4 is able to regulate cell-surface expression of ClC-5 in Xenopus oocytes. Interestingly, in opossum kidney cells derived from proximal tubules, physiological concentrations of albumin stimulate the uptake of albumin (thought to occur via megalin-cubulin receptor), cell-surface expression and monoubiquitylation level of ClC-5, and the expression of Nedd4-2 (29). When a catalytically inactive Nedd4-2 mutant is overexpressed, or Nedd4-2 is suppressed by RNA interference, the uptake of albumin is impaired, suggesting that Nedd4-2 is somehow implicated in this process (29).

Connexin43
Connexin43 (Cx43) is a member of the gap-junction proteins that form complexes linking the cytoplasms of adjacent cells (79). These intercellular channels allow the passage of low-molecular-weight molecules between cells and play a role in many cellular processes such as embryonic development and synchronous contraction of cardiac and smooth muscle cells. Of interest, Cx43 are relatively short-lived proteins, with a half-life as short as 1.5 h. In fact, Cx43 has been shown to be ubiquitylated (45, 49, 50) and to be degraded by both the proteasome and lysosome (46, 80). Cx43 also contains at its COOH terminus a PY motif (shown in bold: PPGYKLV) that overlaps with a tyrosine-based sorting motif (shown in italic, YXX{phi}) (10). This region has been shown to control stability of Cx43 and to target Cx43 for lysosomal degradation (80). However, surprisingly it is the tyrosine-based sorting signal, and not PY motif-dependent ubiquitylation, that controls the targeting to and the degradation in the lysosome. Ubiquitylation and the proteasome may also play a role, but the E3 enzyme(s) involved in this process remain to be identified.


   Ubiquitylation of Ion Channels by the ERAD Pathway
Top
 Introduction
 Ubiquitylation of Ion Channels...
 Ubiquitylation of Ion Channels...
ERAD-Mediated Ubiquitylation of...
 ERAD-Mediated Ubiquitylation of...
 Ubiquitylated Ion Channels:...
 Conclusions and Perspectives
 References
 
Because ion channels are formed by membrane proteins that are assembled and matured during a sequence of many different processes (e.g., correct folding and assembly, glycosylation, lipid modification), their biogenesis has to be tightly controlled. It is well established that such "quality control" of membrane proteins is assured in the endoplasmic reticulum (ER), where the proteins are synthesized and simultaneously translocated into the membrane. Unassembled and/or misfolded proteins are recognized by this system and are subsequently retrotranslocated and degraded by the ubiquitin proteasome system (UPS; FIGURES 2Go AND 3Go). This process is called ER-associated degradation (ERAD) (18). ERAD has been shown to play an important role in eliminating ion channels that are misfolded because they contain incorrect amino acid sequences encoded by mutated genes. Thereby the studies with respect to the chloride channel CFTR have been instrumental for the understanding of the molecular mechanisms of ERAD. CFTR and two other examples of such genetic channelopathies are presented below. In addition, more recently the ERAD mechanism has also been proposed to be involved in determining the assembly efficiency of multimeric ion channels (12, 90). Clearly, such a mechanism represents a new and interesting concept that merits further investigation.



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  		FIGURE 3. Molecular mechanisms involved in CFTR ER-associated degradation
Misfolded CFTR, comprising the cytosolic nucleotide-binding domains 1 and 2 (NBD 1 and 2) and the regulatory R domain, is recognized by the cytosolic chaperone Hsc70 and the cochaperone Hsp40, which recruits the ubiquitin-protein ligase CHIP, containing a U-Box, and the E2 enzyme UbcH5a. Other E3 ligases, such as Doa10 (in concert with Ubc6) and Der3/Hrp1 and SCF(Fbx2) likely play a role in recognition and ubiquitylation of CFTR. Upon ubiquitylation CFTR is retrotranslocated through the transmembrane protein channel Sec61 with the assistance of the cytosolic p97/Ufd1/Npl4 complex. P97/Ufd1/Np14, the Hsc70 associated protein BAG-1, and likely the polyubiquitin chains of CFTR promote the transfer to the proteasome and CFTR degradation.

 

   ERAD-Mediated Ubiquitylation of Misfolded Ion Channels Caused by Mutations
Top
 Introduction
 Ubiquitylation of Ion Channels...
 Ubiquitylation of Ion Channels...
 ERAD-Mediated Ubiquitylation of...
ERAD-Mediated Ubiquitylation of...
 Ubiquitylated Ion Channels:...
 Conclusions and Perspectives
 References
 
CFTR
CFTR is a chloride channel encoded by the gene mutated in cystic fibrosis (CF), an autosomal-recessive disease in which lack of CFTR function at the apical surface of epithelial cells lining lung airways is the major cause of mortality. This defect causes altered hydration of airway epithelia and persistent lung infections (60). CFTR is a glycoprotein of 1,480 amino acids, comprised of two transmembrane regions (each containing six transmembrane helices), two cytoplasmic nucleotide-binding domains (NBDs), and one regulatory (R) region (FIGURE 3Go). The most common mutation in Caucasian CF patients causes the deletion of phenylalanine-508 (CFTR{Delta}F508), located at the first NBD of CFTR. CFTR{Delta}F508 contains a temperature-sensitive folding defect, ultimately causing its retention and premature degradation by ERAD. Importantly, CFTR is a large protein with many transmembrane domains, and because it requires numerous intramolecular contacts, its biogenesis is inefficient and slow, with 60–75% of CFTR and almost 99% of CFTR{Delta}F508 being degraded in the ER (85).

Because of the high frequency of this folding mutant in the population, as well as its important impact on the morbidity of CF patients, the mechanisms of ERAD involving CFTR have been intensively studied. In fact, CFTR was the first membrane protein found to be ubiquitylated during ERAD (33, 86). The molecular events of ERAD of CFTR can be described as follows and are essentially also valid for other ERAD substrates (FIGURE 3Go). In the first step, the cytosolic chaperone and heat-shock protein Hsc70 is recruited by the cochaperone Hsp40 to the ER membrane, where it recognizes and interacts with the unfolded regions of CFTR; i.e., NBD1 and the R domain (55). Then Hsc70 binds to the U-box containing E3 enzyme carboxyl terminus of Hsc70-interacting protein (CHIP) and recruits it to CFTR. This will promote ubiquitylation of CFTR in concert with the E2 enzyme UbcH5a (93). CFTR is then retrotranslocated to the cytosol involving the translocon Sec61, the same protein channel that served insertion into the membrane during biosynthesis (9). During or after retrotranslocation, CFTR is then targeted to the proteasome by the Hsc70-interacting protein Bcl-2-associated athanogene-1 (BAG-1) (3) and by a cytosolic complex (p97/Ufd1/Npl4) that binds both to ubiquitylated CFTR and to the proteasome (25, 91). Other E3 enzymes are also likely involved, namely Doa10 in concert with Ubc6 and Der3/Hrp1 (25), which are both transmembrane proteins. Moreover, on the luminal side CFTR is targeted by the lectin calnexin that interacts with the glycan chains of CFTR, and these glycolytic chains may also interact with the sugar chain-recognizing E3 enzyme Skp1-Cullin1 (F-box protein 2) [SCF(Fbx2)] once the proteins are translocated to the cytosol (92). It has to be noted that ubiquitylation can also regulate CFTR at the plasma membrane. In two recent studies, it was shown that internalized CFTR can either be ubiquitylated and diverted for lysosomal degradation or be recycled back to the cell surface (24, 69).

hERG1
The cardiac voltage-gated potassium channel called human ether-à-go-go-related gene (hERG1; also Kv11.1) mediates an outward current responsible for the repolarization of the cardiac action potential (63). More than 200 mutations in the human gene KCNH2 (encoding hERG1) have been reported to be linked to the congenital long QT syndrome, which is characterized by a prolonged QT interval on the ECG, occurrence of syncope, and sudden cardiac death (39). Many of these KCNH2 mutations are generating misfolded hERG1 channels, and recent studies (19, 26) presented data showing that such mutant channels are degraded by the ERAD pathway upon ubiquitylation of the channel protein in a way very similar to CFTR.

Kv1.1
Finally, >15 point mutations in the gene KCNA1, which encodes the Kv1.1 potassium channel sub-unit, have been found in patients affected by episodic ataxia. This disease is characterized by neurological alterations, including imbalance and uncoordinated movements, and is dominantly transmitted in families. In a study of 14 of the known KCNA1 mutations, Manganas et al. (54) described one COOH-terminally truncated Kv1.1 subunit caused by a nonsense mutation. This mutant Kv1.1 subunit presented several features of misfolded proteins, such as intracellular retention, detergent insolubility, and rescue at lower incubation temperature. Interestingly, cells expressing this mutant Kv1.1 showed protein aggregates that were immunopositive for ubiquitin, suggesting that, also in this case, misfolded Kv1.1 is processed by ERAD and degraded upon its ubiquitylation.

Rescue procedures for misfolded channels
With respect to these channelopathies, many groups are presently focusing on different types of rescue procedures by investigating mutant channels expressed in cell lines or even in vivo in the CFTR mutant channels (16, 17). Two main classes of drugs have been shown to be effective "rescuers": so-called "pharmacological chaperones" and ER calcium-ATPase inhibitors. First, specific membrane-permeable ion-channel ligands, such as astemizole for hERG1 (20, 96) and mexiletine for Nav1.5 (42), have been shown to increase the current mediated by mutated channels, likely by enhancing the trafficking of such channels trapped in the ER. However, since most of these pharmacological chaperones are ion-channel blockers, they cannot be used in a clinical setting, and there is therefore a need to find other drugs with no blocking activity. Second, both thapsigargin and curcumin, which are known to block the ER calcium-ATPase, have also been reported as effective in increasing the current mediated by several misfolded channels (14, 16, 17, 42). The precise mechanism by which a decrease in free ER lumen calcium may interfere with the quality-control processes is not yet understood. However, it has been suggested that this phenomenon relies on the fact that the interaction of CFTR{Delta}F508 with calnexin (FIGURE 3Go), and maybe other luminal ER proteins, is calcium dependent (17). In fact, this is a very active field of research, and one may hope to see, in the near future, novel therapeutic strategies that could be applied to patients.


   ERAD-Mediated Ubiquitylation of Multimeric Ion Channels as a Way to Regulate Biogenesis
Top
 Introduction
 Ubiquitylation of Ion Channels...
 Ubiquitylation of Ion Channels...
 ERAD-Mediated Ubiquitylation of...
 ERAD-Mediated Ubiquitylation of...
Ubiquitylated Ion Channels:...
 Conclusions and Perspectives
 References
 
As mentioned above, one of the major roles of the ubiquitin-proteasome ERAD pathway is to prevent mutant/misfolded proteins from accumulating in the cells. However, another important function of ERAD may consist in regulating the expression of normal (i.e., nonmutated) ion-channel proteins by controlling their biogenesis efficiency. This mechanism may be very important for multimeric ion channels (i.e., made up of several proteins), since the assembly process has been reported to be of low yield and could therefore easily be enhanced.

Nicotinic acetylcholine receptor
This new concept was first proposed for the nicotinic acetylcholine receptor (nAChR), which is a ligand-gated sodium and calcium channel present in the postsynaptic membranes of the neuromuscular junctions. The biogenesis of this channel has been studied in detail, and maturation and assembly of the pentameric nAChR has been shown to be a complex process (84). A recent study (12) presented evidence that ERAD and UPS, by constantly degrading unassembled subunits, appear to regulate the surface density of nAChR in myocytes. The authors propose a model (12) in which assembly of nAChR in the ER and ERAD of unassembled subunits are two concurrent processes that, as a result, may determine the amount of channels found at the synaptic membrane.

ATP-sensitive potassium channels
A similar type of regulation has also been studied for another type of multimeric channel. The ATP-sensitive potassium (KATP) channels are octameric complexes formed by Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits in pancreatic ß-cells and other similar subunit combinations in other tissues (6). These potassium channels are important in cell physiology because they link cell metabolism to electrical activity. It has recently been reported (78, 90) that the UPS is involved in regulating the biogenesis efficiency, and thereby the cell-surface density, of KATP channels in a similar fashion to that reported for the nAChR. In two studies investigating KATP channels of pancreatic ß-cells (90) and neonatal cardiomyocytes (78), proteasome inhibitors were shown to increase the KATP current. In addition, polyubiquitylation of Kir6.2 (78, 90) and SUR1 (90) could be observed using heterologous expression systems.

NMDA receptors
N-methyl-D-aspartate (NMDA) receptors are nonselective cation channels gated by the neurotransmitter glutamate that are mainly concentrated at the postsynaptic densities in neurons. The control of density of this ion channel at the surface of neurons is important for synaptic plasticity and also because they may be involved in cell death in neurodegenerative diseases. NMDA receptors are formed by heterotetramers containing the NR1 subunit. In expression systems, Kato et al. (38) recently showed that the density of NMDA receptors at the postsynaptic densities is regulated by the activity of the Fbx2 ubiquitin ligase that binds to the sugar moieties of NR1 and ubiquitylates it. Interestingly, neuronal activity was shown to enhance the ubiquitylation-dependent degradation of NR1 by Fbx2 (38).


   Ubiquitylated Ion Channels: Unique Descriptions
Top
 Introduction
 Ubiquitylation of Ion Channels...
 Ubiquitylation of Ion Channels...
 ERAD-Mediated Ubiquitylation of...
 ERAD-Mediated Ubiquitylation of...
 Ubiquitylated Ion Channels:...
Conclusions and Perspectives
 References
 
During the past four years, descriptions of ion-channel ubiquitylation in different contexts have been sporadically published. In most cases, however, there was no data available regarding the identity of the enzymes involved in the ubiquitylation and deubiquitylation processes, and as a result, further studies are clearly needed to address these open questions. These channels, and the relevant references, are listed in Table 1Go.


   Conclusions and Perspectives
Top
 Introduction
 Ubiquitylation of Ion Channels...
 Ubiquitylation of Ion Channels...
 ERAD-Mediated Ubiquitylation of...
 ERAD-Mediated Ubiquitylation of...
 Ubiquitylated Ion Channels:...
 Conclusions and Perspectives
References
 
Although we have made considerable progress in the understanding of ubiquitylated ion channels, there are many open questions regarding these important processes. Ubiquitylation has now been shown for many different types of ion channels (Table 1Go) and in numerous different cellular contexts, such as regulation of membrane abundance via influence of the biogenesis or internalization pathways, regulation of activity, and general protein stability. Some of these ubiquitylation processes are regulated (action of hormones or different cellular stresses), and other types seem to be "constitutive." However, thus far we do not know how common these mechanisms are and whether all ion channels are regulated by their ubiquitylation. Moreover, for most of the studied channels we do not unambiguously know the identity of the ubiquitin-protein ligase(s) that is involved in the ubiquitylation event. Are these mostly Nedd4/Nedd4-like proteins, as suggested by the extensive work of the Lang laboratory (82)? Or are other E3 enzymes, such as CHIP, equally important? Generally, ubiquitylation of these channels leads either to their degradation by the proteasome (during ERAD) or to their internalization, thereby targeting them for lysosomal degradation. Are other types of proteases also involved? It is interesting to note that extracellular proteases can also regulate channel activity, as shown for ENaC, which becomes stimulated by the serine protease Cap1 (81).

From numerous studies of receptor ubiquitylation, we know that these receptors become monoubiquitylated, causing internalization. Monoubiquitylation is also required for targeting these receptors to the multiple-vesicle-body pathway (28), eventually leading to lysosomal degradation (FIGURE 2Go). The molecular events and the proteins implicated in these pathways have been extensively studied (8); although it is likely that ion channels follow the same fate, this has not been demonstrated yet. Similarly to the other types of posttranslational modifications of proteins such as phosphorylation and methylation, for example, the level of ubiquitylation of proteins is ultimately determined by the activity of ubiquitin-protein ligases and DUBs (4). Thus far, no such DUBs deubiquitylating ion channels have been described, but there is little doubt that they exist. Finally, the modification of the K2P1 potassium channel by the ubiquitin-like protein SUMO has recently been described, and it was shown that such sumoylation could "silence" these channels present at the cell membrane (59). It will be interesting to see whether such ion-channel modifications by ubiquitin-like proteins represent a general mechanism and what could be their physiological roles.

In conclusion, this review illustrates that the activity and fate of ion channels can be regulated by their ubiquitylation in several different cellular contexts. However, it will only be in the next few years that, thanks to the future studies of many researchers, we should be able to better understand the details, the complexity, and precise roles of this protein modification in physiology.


   Acknowledgments
 
We are grateful to R. Behar and K. Geering for their useful comments on this manuscript, as well as to the anonymous reviewers for their valuable suggestions.

We would like to apologize to the many researchers in this field whose studies could not be cited due space limitation.

This work has been supported in part by grants of the Swiss National Science Foundation to H. Abriel (SNF-Professorship #632-66149.01) and O. Staub (3100A0-103779/1).


   References
Top
 Introduction
 Ubiquitylation of Ion Channels...
 Ubiquitylation of Ion Channels...
 ERAD-Mediated Ubiquitylation of...
 ERAD-Mediated Ubiquitylation of...
 Ubiquitylated Ion Channels:...
 Conclusions and Perspectives
 References
 

  1. Abriel H, Kamynina E, Horisberger JD, and Staub O. Regulation of the cardiac voltage-gated Na+ channel (H1) by the ubiquitin-protein ligase Nedd4. FEBS Lett 466: 377–380, 2000.[CrossRef][Web of Science][Medline]
  2. Abriel H, Loffing J, Rebhun JF, Pratt JH, Schild L, Horisberger JD, Rotin D, and Staub O. Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle’s syndrome. J Clin Invest 103: 667–673, 1999.[Web of Science][Medline]
  3. Alberti S, Demand J, Esser C, Emmerich N, Schild H, and Hohfeld J. Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome. J Biol Chem 277: 45920–45927, 2002.[Abstract/Free Full Text]
  4. Amerik AY and Hochstrasser M. Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 1695: 189–207, 2004.[Medline]
  5. Ashcroft FM. Ion Channels and Disease. San Diego: Academic, 2000.
  6. Ashcroft FM. ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Invest 115: 2047–2058, 2005.[CrossRef][Web of Science][Medline]
  7. Auberson M, Hoffmann-Pochon N, Vandewalle A, Kellenberger S, and Schild L. Epithelial Na+ channel mutants causing Liddle’s syndrome retain ability to respond to aldosterone and vasopressin. Am J Physiol Renal Physiol 285: F459–F471, 2003.[Abstract/Free Full Text]
  8. Babst M. A protein’s final ESCRT. Traffic 6: 2–9, 2005.[CrossRef][Web of Science][Medline]
  9. Bebok Z, Mazzochi C, King SA, Hong JS, and Sorscher EJ. The mechanism underlying cystic fibrosis transmembrane conductance regulator transport from the endoplasmic reticulum to the proteasome includes sec61ß and a cytosolic, deglycosylated intermediary. J Biol Chem 273: 29873–29878, 1998.[Abstract/Free Full Text]
  10. Bonifacino JS and Dell’Angelica EC. Molecular bases for the recognition of tyrosine-based sorting signals. J Cell Biol 145: 923–926, 1999.[Free Full Text]
  11. Chen H, Ross CA, Wang N, Huo Y, MacKinnon DF, Potash JB, Simpson SG, McMahon FJ, DePaulo J Jr, and McInnis MG. NEDD4L on human chromosome 18q21 has multiple forms of transcripts and is a homologue of the mouse Nedd4-2 gene. Eur J Hum Genet 9: 922–930, 2001.[CrossRef][Web of Science][Medline]
  12. Christianson JC and Green WN. Regulation of nicotinic receptor expression by the ubiquitin-proteasome system. EMBO J 23: 4156–4165, 2004.[CrossRef][Web of Science][Medline]
  13. Debonneville C, Flores SY, Kamynina E, Plant PJ, Tauxe C, Thomas MA, Munster C, Chraibi A, Pratt JH, Horisberger JD, Pearce D, Loffing J, and Staub O. Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. EMBO J 20: 7052–7059, 2001.[CrossRef][Web of Science][Medline]
  14. Delisle BP, Anderson CL, Balijepalli RC, Anson BD, Kamp TJ, and January CT. Thapsigargin selectively rescues the trafficking defective LQT2 channels G601S and F805C. J Biol Chem 278: 35749–35754, 2003.[Abstract/Free Full Text]
  15. Dinudom A, Harvey KF, Komwatana P, Young JA, Kumar S, and Cook DI. Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+. Proc Natl Acad Sci USA 95: 7169–7173, 1998.[Abstract/Free Full Text]
  16. Egan ME, Glockner-Pagel J, Ambrose C, Cahill PA, Pappoe L, Balamuth N, Cho E, Canny S, Wagner CA, Geibel J, and Caplan MJ. Calcium-pump inhibitors induce functional surface expression of {Delta}F508-CFTR protein in cystic fibrosis epithelial cells. Nat Med 8: 485–492, 2002.[CrossRef][Web of Science][Medline]
  17. Egan ME, Pearson M, Weiner SA, Rajendran V, Rubin D, Glockner-Pagel J, Canny S, Du K, Lukacs GL, and Caplan MJ. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science 304: 600–602, 2004.[Abstract/Free Full Text]
  18. Ellgaard L and Helenius A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4: 181–191, 2003.[CrossRef][Web of Science][Medline]
  19. Ficker E, Dennis AT, Wang L, and Brown AM. Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG. Circ Res 92: e87–e100, 2003.[Abstract/Free Full Text]
  20. Ficker E, Obejero-Paz CA, Zhao S, and Brown AM. The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. J Biol Chem 277: 4989–4998, 2002.[Abstract/Free Full Text]
  21. Firsov D, Schild L, Gautschi I, Merillat AM, Schneeberger E, and Rossier BC. Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach. Proc Natl Acad Sci USA 93: 15370–15375, 1996.[Abstract/Free Full Text]
  22. Flores SY, Loffing-Cueni D, Kamynina E, Daidie D, Gerbex C, Chabanel S, Dudler J, Loffing J, and Staub O. Aldosterone-induced serum and gluco-corticoid-induced kinase 1 expression is accompanied by Nedd4-2 phosphorylation and increased Na+ transport in cortical collecting duct cells. J Am Soc Nephrol 16: 2279–2287, 2005.[Abstract/Free Full Text]
  23. Fotia AB, Ekberg J, Adams DJ, Cook DI, Poronnik P, and Kumar S. Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2. J Biol Chem 279: 28930–28935, 2004.[Abstract/Free Full Text]
  24. Gentzsch M, Chang XB, Cui L, Wu Y, Ozols VV, Choudhury A, Pagano RE, and Riordan JR. Endocytic trafficking routes of wild type and {Delta}f508 cystic fibrosis transmembrane conductance regulator. Mol Biol Cell 15: 2684–2696, 2004.[Abstract/Free Full Text]
  25. Gnann A, Riordan JR, and Wolf DH. Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast. Mol Biol Cell 15: 4125–4135, 2004.[Abstract/Free Full Text]
  26. Gong Q, Keeney DR, Molinari M, and Zhou Z. Degradation of trafficking-defective long qt syndrome type II mutant channels by the ubiquitin-proteasome pathway. J Biol Chem 280: 19419–19425, 2005.[Abstract/Free Full Text]
  27. Goulet CC, Volk KA, Adams CM, Prince LS, Stokes JB, and Snyder PM. Inhibition of the epithelial Na+ channel by interaction of Nedd4 with a PY motif deleted in Liddle’s syndrome. J Biol Chem 273: 30012–30017, 1998.[Abstract/Free Full Text]
  28. Hicke L. Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2: 195–201, 2001.[CrossRef][Web of Science][Medline]
  29. Hryciw DH, Ekberg J, Lee A, Lensink IL, Kumar S, Guggino WB, Cook DI, Pollock CA, and Poronnik P. Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells. J Biol Chem 279: 54996–55007, 2004..[Abstract/Free Full Text]
  30. Huibregtse JM, Scheffner M, Beaudenon S, and Howley PM. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci USA 92: 2563–2567, 1995.[Abstract/Free Full Text]
  31. Ingham RJ, Gish G, and Pawson T. The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture. Oncogene 23: 1972–1984, 2004.[CrossRef][Web of Science][Medline]
  32. Itani OA, Stokes JB, and Thomas CP. Nedd4-2 isoforms differentially associate with ENaC and regulate its activity. Am J Physiol Renal Physiol. In press.
  33. Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, and Riordan JR. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 83: 129–135, 1995.[CrossRef][Web of Science][Medline]
  34. Jentsch TJ, Poet M, Fuhrmann JC, and Zdebik AA. Physiological functions of ClC channels gleaned from human genetic disease and mouse models. Annu Rev Physiol 67: 779–807, 2005.[CrossRef][Web of Science][Medline]
  35. Kamynina E, Debonneville C, Bens M, Vandewalle A, and Staub O. A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J 15: 204–214, 2001.[Abstract/Free Full Text]
  36. Kamynina E, Tauxe C, and Staub O. Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na+ channel regulation. Am J Physiol Renal Physiol 281: F469–F477, 2001.[Abstract/Free Full Text]
  37. Kanelis V, Rotin D, and Forman-Kay JD. Solution structure of a Nedd4 WW domain-ENaC peptide complex. Nat Struct Biol 8: 407–412, 2001.[CrossRef][Web of Science][Medline]
  38. Kato A, Rouach N, Nicoll RA, and Bredt DS. Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination. Proc Natl Acad Sci USA (April 4, 2005); doi:10.1073/pnas.0501769102.[Abstract/Free Full Text]
  39. Keating MT and Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104: 569–580, 2001.[CrossRef][Web of Science][Medline]
  40. Kellenberger S, Gautschi I, Rossier BC, and Schild L. Mutations causing Liddle syndrome reduce sodium-dependent downregulation of the epithelial sodium channel in the Xenopus oocyte expression system. J Clin Invest 101: 2741–2750, 1998.[Web of Science][Medline]
  41. Kellenberger S and Schild L. Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol Rev 82: 735–767, 2002.[Abstract/Free Full Text]
  42. Keller DI, Rougier JS, Kucera JP, Benammar N, Fressart V, Guicheney P, Madle A, Fromer M, Schlapfer J, and Abriel H. Brugada syndrome and fever: genetic and molecular characterization of patients carrying SCN5A mutations. Cardiovasc Res 67: 510–519, 2005.[Abstract/Free Full Text]
  43. Khan MT and Joseph SK. Proteolysis of type I inositol 1,4,5-trisphosphate receptor in WB rat liver cells. Biochem J 375: 603–611, 2003.[CrossRef][Web of Science][Medline]
  44. Koegl M, Hoppe T, Schlenker S, Ulrich HD, Mayer TU, and Jentsch S. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96: 635–644, 1999.[CrossRef][Web of Science][Medline]
  45. Laing JG and Beyer EC. The gap junction protein connexin43 is degraded via the ubiquitin proteasome pathway. J Biol Chem 270: 26399–26403, 1995.[Abstract/Free Full Text]
  46. Laing JG, Tadros PN, Westphale EM, and Beyer EC. Degradation of connexin43 gap junctions involves both the proteasome and the lysosome. Exp Cell Res 236: 482–492, 1997.[CrossRef][Web of Science][Medline]
  47. Lehmann-Horn F and Jurkat-Rott K. Voltage-gated ion channels and hereditary disease. Physiol Rev 79: 1317–1372, 1999.[Abstract/Free Full Text]
  48. Leitch V, Agre P, and King LS. Altered ubiquitination and stability of aquaporin-1 in hypertonic stress. Proc Natl Acad Sci USA 98: 2894–2898, 2001.[Abstract/Free Full Text]
  49. Leithe E and Rivedal E. Epidermal growth factor regulates ubiquitination, internalization and proteasome-dependent degradation of connexin43. J Cell Sci 117: 1211–1220, 2004.[Abstract/Free Full Text]
  50. Leithe E and Rivedal E. Ubiquitination and down-regulation of gap junction protein connexin-43 in response to 12-O-tetradecanoylphorbol 13-acetate treatment. J Biol Chem 279: 50089–50096, 2004.[Abstract/Free Full Text]
  51. Levy F, Muehlethaler K, Salvi S, Peitrequin AL, Lindholm CK, Cerottini JC, and Rimoldi D. Ubiquitylation of a melanosomal protein by HECT-E3 ligases serves as sorting signal for lysosomal degradation. Mol Biol Cell 16: 1777–1787, 2005.[Abstract/Free Full Text]
  52. Lin DH, Sterling H, Wang Z, Babilonia E, Yang B, Dong K, Hebert SC, Giebisch G, and Wang WH. ROMK1 channel activity is regulated by monoubiquitination. Proc Natl Acad Sci USA (March 14, 2005); doi:10.1073/pnas.0409767102.[Abstract/Free Full Text]
  53. Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, and Thakker RV. A common molecular basis for three inherited kidney stone diseases. Nature 379: 445–449, 1996.[CrossRef][Medline]
  54. Manganas LN, Akhtar S, Antonucci DE, Campomanes CR, Dolly JO, and Trimmer JS. Episodic ataxia type-1 mutations in the Kv1.1 potassium channel display distinct folding and intracellular trafficking properties. J Biol Chem 276: 49427–49434, 2001.[Abstract/Free Full Text]
  55. Meacham GC, Lu Z, King S, Sorscher E, Tousson A, and Cyr DM. The Hdj-2/Hsc70 chaperone pair facilitates early steps in CFTR biogenesis. EMBO J 18: 1492–1505, 1999.[CrossRef][Web of Science][Medline]
  56. Nalefskie A and Falke JJ. The C2 domain calcium-binding motif: structural and functional diversity. Protein Sci 5: 2375–2390, 1996.[Web of Science][Medline]
  57. Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem 70: 503–533, 2001.[CrossRef][Web of Science][Medline]
  58. Picollo A and Pusch M. Chloride/proton antiporter activity of mammalian ClC proteins ClC-4 and ClC-5. Nature 436: 420–423, 2005.[CrossRef][Medline]
  59. Rajan S, Plant LD, Rabin ML, Butler MH, and Goldstein SAN. Sumoylation silences the plasma membrane leak K+ channel K2P1. Cell 121: 37–47, 2005.[CrossRef][Web of Science][Medline]
  60. Riordan JR. Assembly of functional CFTR chloride channels. Annu Rev Physiol 67: 701–718, 2005.[CrossRef][Web of Science][Medline]
  61. Rotin D, Staub O, and Haguenauer-Tsapis R. Ubiquitination and endocytosis of plasma membrane proteins: role of Nedd4/Rsp5p family of ubiquitin-protein ligases. J Membr Biol 176: 1–17, 2000.[CrossRef][Web of Science][Medline]
  62. Rougier JS, van Bemmelen MX, Bruce MC, Jespersen T, Gavillet B, Apotheloz F, Cordonier S, Staub O, Rotin D, and Abriel H. Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins. Am J Physiol Cell Physiol 288: C692–C701, 2005.[Abstract/Free Full Text]
  63. Sanguinetti MC, Curran ME, Spector PS, and Keating MT. Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci USA 93: 2208–2212, 1996.[Abstract/Free Full Text]
  64. Scheel O, Zdebik AA, Lourdel S, and Jentsch TJ. Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature 436: 424–427, 2005.[CrossRef][Medline]
  65. Schild L, Canessa CM, Shimkets RA, Gautschi I, Lifton RP, and Rossier BC. A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system. Proc Natl Acad Sci USA 92: 5699–5703, 1995.[Abstract/Free Full Text]
  66. Schild L, Lu Y, Gautschi I, Schneeberger E, Lifton RP, and Rossier BC. Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J 15: 2381–2387, 1996.[Web of Science][Medline]
  67. Schwake M, Friedrich T, and Jentsch TJ. An internalization signal in ClC-5, an endosomal Cl-channel mutated in dent’s disease. J Biol Chem 276: 12049–12054, 2001.[Abstract/Free Full Text]
  68. Schwartz DC and Hochstrasser M. A superfamily of protein tags: ubiquitin, SUMO and related modifiers. Trends Biochem Sci 28: 321–328, 2003.[CrossRef][Web of Science][Medline]
  69. Sharma M, Pampinella F, Nemes C, Benharouga M, So J, Du K, Bache KG, Papsin B, Zerangue N, Stenmark H, and Lukacs GL. Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes. J Cell Biol 164: 923–933, 2004.[Abstract/Free Full Text]
  70. Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JRJ, Ulick S, Milora RV, and Findling JW. Liddle’s syndrome: heritable human hypertension caused by mutations in the ß subunit of the epithelial sodium channel. Cell 79: 407–414, 1994.[CrossRef][Web of Science][Medline]
  71. Snyder PM, Olson DR, and Thomas BC. Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel. J Biol Chem 277: 5–8, 2002.[Abstract/Free Full Text]
  72. Snyder PM, Price MP, McDonald FJ, Adams CM, Volk KA, Zeiher BG, Stokes JB, and Welsh MJ. Mechanism by which Liddle’s syndrome mutations increase activity of a human epithelial Na+ channel. Cell 83: 969–978, 1995.[CrossRef][Web of Science][Medline]
  73. Snyder PM, Steines JC, and Olson DR. Relative contribution of Nedd4 and Nedd4-2 to ENaC regulation in epithelia determined by RNA interference. J Biol Chem 279: 5042–5046, 2004.[Abstract/Free Full Text]
  74. Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, and Rotin D. WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle’s syndrome. EMBO J 15: 2371–2380, 1996.[Web of Science][Medline]
  75. Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, and Rotin D. Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J 16: 6325–6336, 1997.[CrossRef][Web of Science][Medline]
  76. Staub O and Rotin D. WW domains. Structure 4: 495–499, 1996.[Medline]
  77. Staub O and Verrey F. The impact of Nedd4 proteins and Sgk kinases on epithelial Na+ transport in the distal nephron. J Am Soc Nephrol. In press.
  78. Tanaka H, Miake J, Notsu T, Sonyama K, Sasaki N, Iitsuka K, Kato M, Taniguchi Si Igawa O, and Yoshida A. Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na+ channel blocker aprindine. Biochem Biophys Res Commun 331: 1001–1006, 2005.[CrossRef][Web of Science][Medline]
  79. Thomas MA, Huang S, Cokoja A, Riccio O, Staub O, Suter S, and Chanson M. Interaction of connexins with protein partners in the control of channel turnover and gating. Biol Cell 94: 445–456, 2002.[CrossRef][Web of Science][Medline]
  80. Thomas MA, Zosso N, Scerri I, Demaurex N, Chanson M, and Staub O. A tyrosine-based sorting signal is involved in connexin43 stability and gap junction turnover. J Cell Sci 116: 2213–2222, 2003.[Abstract/Free Full Text]
  81. Vallet V, Chraibi A, Gaeggeler HP, Horisberger JD, and Rossier BC. An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature 389: 607–610, 1997.[CrossRef][Medline]
  82. Vallon V, Wulff P, Huang DY, Loffing J, Volkl H, Kuhl D, and Lang F. Role of Sgk1 in salt and potassium homeostasis. Am J Physiol Regul Integr Comp Physiol 288: R4–R10, 2005.[Abstract/Free Full Text]
  83. Van Bemmelen MX, Rougier JS, Gavillet B, Apotheloz F, Daidie D, Tateyama M, Rivolta I, Thomas MA, Kass RS, Staub O, and Abriel H. Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination. Circ Res 95: 284–291, 2004.[Abstract/Free Full Text]
  84. Wanamaker CP, Christianson JC, and Green WN. Regulation of nicotinic acetylcholine receptor assembly. Ann NY Acad Sci 998: 66–80, 2003.[CrossRef][Web of Science][Medline]
  85. Ward CL and Kopito RR. Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild-type and mutant proteins. J Biol Chem 269: 25710–25718, 1994.[Abstract/Free Full Text]
  86. Ward CL, Omura S, and Kopito RR. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83: 121–127, 1995.[CrossRef][Web of Science][Medline]
  87. Webster JM, Tiwari S, Weissman AM, and Wojcikiewicz RJH. Inositol 1,4,5-trisphosphate receptor ubiquitination is mediated by mammalian Ubc7, a component of the endoplasmic reticulum-associated degradation pathway, and is inhibited by chelation of intracellular Zn2+. J Biol Chem 278: 38238–38246, 2003.[Abstract/Free Full Text]
  88. Wojcikiewicz RJH, Xu Q, Webster JM, Alzayady K, and Gao C. Ubiquitination and proteasomal degradation of endogenous and exogenous inositol 1,4,5-trisphosphate receptors in {alpha} T3-1 anterior pituitary cells. J Biol Chem 278: 940–947, 2003.[Abstract/Free Full Text]
  89. Xu Q, Farah M, Webster JM, and Wojcikiewicz RJH. Bortezomib rapidly suppresses ubiquitin thiolesterification to ubiquitin-conjugating enzymes and inhibits ubiquitination of histones and type I inositol 1,4,5-trisphosphate receptor. Mol Cancer Ther 3: 1263–1269, 2004.[Abstract/Free Full Text]
  90. Yan FF, Lin CW, Cartier EA, and Shyng SL. A role of the ubiquitin-proteasome degradation pathway in the biogenesis efficiency of ß-cell ATP-sensitive potassium channels. Am J Physiol Cell Physiol (June 29, 2005); doi:10.1152/ajp-cell.00240.2005.
  91. Ye Y, Meyer HH, and Rapoport TA. Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J Cell Biol 162: 71–84, 2003.[Abstract/Free Full Text]
  92. Yoshida Y, Chiba T, Tokunaga F, Kawasaki H, Iwai K, Suzuki T, Ito Y, Matsuoka K, Yoshida M, Tanaka K, and Tai T. E3 ubiquitin ligase that recognizes sugar chains. Nature 418: 438–442, 2002.[CrossRef][Medline]
  93. Younger JM, Ren HY, Chen L, Fan CY, Fields A, Patterson C, and Cyr DM. A foldable CFTR{Delta}F508 biogenic intermediate accumulates upon inhibition of the Hsc70-CHIP E3 ubiquitin ligase. J Cell Biol 167: 1075–1085, 2004.[Abstract/Free Full Text]
  94. Yu F and Catterall W. Overview of the voltage-gated sodium channel family. Genome Biol 4: 207, 2003.[CrossRef][Medline]
  95. Zheng YJ, Furukawa T, Ogura T, Tajimi K, and Inagaki N. M phase-specific expression and phosphorylation-dependent ubiquitination of the ClC-2 channel. J Biol Chem 277: 32268–32273, 2002.[Abstract/Free Full Text]
  96. Zhou Z, Gong Q, and January CT. Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological and temperature effects. J Biol Chem 274: 31123–31126, 1999.[Abstract/Free Full Text]



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