The role of the ubiquitin proteasome system in Alzheimer's disease.

Today, Alzheimer's disease (AD) is one of the most important age-related neurodegenerative diseases, but its etiology remains still unknown. Since the discovery that the hallmark structures of this disease i.e. the formation of amyloid fibers could be the product of ubiquitin-mediated protein degradation defects, it has become clear that the ubiquitin-proteasome system (UPS), usually essential for protein repair, turnover and degradation, is perturbed in this disease. Different aspects of normal and pathological aging are discussed with respect to protein repair and degradation via the UPS, as well as consequences of a deficit in the UPS in AD. Selective protein oxidation may cause protein damage, or protein mutations may induce a dysfunction of the proteasome. Such events eventually lead to activation of cell death pathways and to an aberrant aggregation or incorporation of ubiquitinated proteins into hallmark structures. Aggresome formation is also observed in other neurodegenerative diseases, suggesting that an activation of similar mechanisms must occur in neurodegeneration as a basic phenomenon. It is essential to discuss therapeutic ways to investigate the UPS dysfunction in the human brain and to identify specific targets to hold or stop cell decay.

Typing Candida albicans oral isolates from human immunodeficiency virus-infected patients by multilocus enzyme electrophoresis and DNA fingerprinting.

A total of 189 Candida albicans isolates have been typed by multilocus enzyme electrophoresis. The results obtained confirm the clonal mode of reproduction of C. albicans. The C. albicans populations found in the oropharynx of human immunodeficiency virus (HIV)-infected patients, in the oropharynx of healthy carriers, or in association with invasive candidiasis could not be distinguished. No clone or group of clones could be associated with the appearance of clinical disorders or with a reduced in vitro susceptibility to the antifungal agent fluconazole. Multiple and sequential oral isolates from 24 HIV-infected patients were also typed by restriction enzyme analysis with the enzymes EcoRI and HinfI and by use of the Ca3 repetitive probe. The results obtained by the combination of all three typing methods show that all but one patient each carried a unique major C. albicans clone in their oropharynx. The 21 patients with sequential isolates had the same C. albicans clones in their throats during recurrent oropharyngeal candidiasis episodes, independently of clinical status or of changes of in vitro susceptibility to fluconazole. Finally, several isolates of the same C. albicans clone found simultaneously in the oropharynx of a patient may present different levels of susceptibility to fluconazole.

Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis.

BACKGROUND: The excess in cardiovascular risk in patients with rheumatoid arthritis provides a strong rationale for early therapeutical interventions. In view of the similarities between atherosclerosis and rheumatoid arthritis and the proven benefit of angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease, it was the aim of the present study to delineate the impact of ramipril on endothelial function as well as on markers of inflammation and oxidative stress in patients with rheumatoid arthritis. METHODS AND RESULTS: Eleven patients with rheumatoid arthritis were included in this randomized, double-blind, crossover study to receive ramipril in an uptitration design (2.5 to 10 mg) for 8 weeks followed by placebo, or vice versa, on top of standard antiinflammatory therapy. Endothelial function assessed by flow-mediated dilation of the brachial artery, markers of inflammation and oxidative stress, and disease activity were investigated at baseline and after each treatment period. Endothelial function assessed by flow-mediated dilation increased from 2.85+/-1.49% to 4.00+/-1.81% (P=0.017) after 8 weeks of therapy with ramipril but did not change with placebo (from 2.85+/-1.49% to 2.84+/-2.47%; P=0.88). Although systolic blood pressure and heart rate remained unaltered, diastolic blood pressure decreased slightly from 78+/-7 to 74+/-6 mm Hg (P=0.03). Tumor necrosis factor-alpha showed a significant inverse correlation with flow-mediated dilation (r=-0.408, P=0.02), and CD40 significantly decreased after ramipril therapy (P=0.049). CONCLUSIONS: Angiotensin-converting enzyme inhibition with 10 mg/d ramipril for 8 weeks on top of current antiinflammatory treatment markedly improved endothelial function in patients with rheumatoid arthritis. This finding suggests that angiotensin-converting enzyme inhibition may provide a novel strategy to prevent cardiovascular events in these patients.

Ubiquitination of the Epstein-Barr virus-encoded latent membrane protein 1 depends on the integrity of the TRAF binding site.

The latent membrane protein 1 (LMP1) encoded by the Epstein-Barr virus functions as a constitutively activated receptor of the tumor necrosis factor receptor family. LMP1 is a short-lived protein that is ubiquitinated and degraded by the proteasome. We have previously shown that LMP1 recruits the adapter protein tumor necrosis factor receptor-associated factor 3 (TRAF3) to lipid rafts. To test if TRAFs are involved in LMP1's ubiquitination, we have mutated the LMP1 CTAR1 site that has been identified as a TRAF binding site. We show that the CTAR1 mutant (CTAR1(-)) is expressed after transfection at a similar level to wild-type LMP1, and behaves as wild-type LMP1 with respect to membrane localization. However, CTAR1(-) does not bind TRAF3. We demonstrate that ubiquitination of CTAR1(-) is significantly reduced when compared to wild-type LMP1. In addition, the expression of wild-type LMP1 induces the ubiquitination, an effect that is significantly reduced when the CTAR1(-) is expressed. Taken together, our results suggest that TRAF proteins are involved in the ubiquitination of LMP1, and that their binding to LMP1 may facilitate their own ubiquitination.

Involvement of the kallikrein-kinin system in the antihypertensive effect of the angiotensin converting enzyme inhibitors.

1. Studies were performed in normal subjects and in rats to assess the effect of angiotensin converting enzyme (ACE) inhibition on the kallikrein-kinin system. As ACE is identical to kininase II, one of the enzymes physiologically involved in bradykinin degradation, bradykinin may be expected to accumulate during ACE inhibition. 2. A competitive antagonist of bradykinin was used to explore in unanaesthetized rats the contribution of circulating bradykinin to blood pressure control under ACE inhibition. 3. No evidence was found for a role of this vasodilating peptide in the blood pressure lowering effect of acute ACE inhibition. 4. The plasma activity of carboxypeptidase N (= kininase I), another pathway of bradykinin degradation, remained intact during a 1 week course of treatment with an ACE inhibitor in normal subjects. This therefore indicates that bradykinin formed during ACE inhibition can still be metabolized.

Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: Modulation in the spared nerve injury model of neuropathic pain.

Neuronal hyperexcitability following peripheral nerve lesions may stem from altered activity of voltage-gated sodium channels (VGSCs), which gives rise to allodynia or hyperalgesia. In vitro, the ubiquitin ligase Nedd4-2 is a negative regulator of VGSC α-subunits (Na(v)), in particular Na(v)1.7, a key actor in nociceptor excitability. We therefore studied Nedd4-2 in rat nociceptors, its co-expression with Na(v)1.7 and Na(v)1.8, and its regulation in pathology. Adult rats were submitted to the spared nerve injury (SNI) model of neuropathic pain or injected with complete Freund's adjuvant (CFA), a model of inflammatory pain. L4 dorsal root ganglia (DRG) were analyzed in sham-operated animals, seven days after SNI and 48h after CFA with immunofluorescence and Western blot. We observed Nedd4-2 expression in almost 50% of DRG neurons, mostly small and medium-sized. A preponderant localization is found in the non-peptidergic sub-population. Additionally, 55.7±2.7% and 55.0±3.6% of Nedd4-2-positive cells are co-labeled with Na(v)1.7 and Na(v)1.8 respectively. SNI significantly decreases the proportion of Nedd4-2-positive neurons from 45.9±1.9% to 33.5±0.7% (p<0.01) and the total Nedd4-2 protein to 44%±0.13% of its basal level (p<0.01, n=4 animals in each group, mean±SEM). In contrast, no change in Nedd4-2 was found after peripheral inflammation induced by CFA. These results indicate that Nedd4-2 is present in nociceptive neurons, is downregulated after peripheral nerve injury, and might therefore contribute to the dysregulation of Na(v)s involved in the hyperexcitability associated with peripheral nerve injuries.

Spirometric abnormalities in patients with Fabry disease and effect of enzyme replacement therapy

Aim: Fabry disease is an X-linked genetic disorder due to deficiency of the lysosomal enzyme a-galactosidase A, which leads to the accumulation of neutral glycosphingolipids within the lysosomes of almost all tissues. Clinical manifestations usually include acroparaesthesia, renal insufficiency and cardiomyopathy. Recently, pulmonary manifestations consisting of progressive obstructive airway disease have been reported. The aim of this study was to analyse the cross-sectional prevalence of airflow obstruction in a Swiss cohort of patients, and in selected cases, to evaluate the impact of enzyme replacement therapy (ERT) with agalsidase alfa (ReplagalTM; TKT - 5S). Methods: Forty-four patients (27 men, 17 women) were included in the study and received pulmonary function testing. Fifteen patients underwent spirometry after ERT. Results: Twelve patients (nine men) had chronic obstructive pulmonary disease according to the Global Obstructive Lung Disease (GOLD) initiative criteria: forced expiratory volume (FEV1)/forced vital capacity (FVC) 50.7), but only one was an active smoker and one a previous smoker. FEV1/ FVC as percentage predicted was weakly correlated with age (r=0.42, p=0.005, calculated by Pearson product-moment correlation), demonstrating that airway obstruction occurs in the late stages of the disease. Median FEV1 in patients with obstruction was 67% of predicted (range, 45-90%). Reversibility of FEV1 after b2-agonist inhalation never exceeded 8% of predicted. Diffusing capacity of the lung for carbon monoxide (DLCO) was measured in 13 individuals with a median of 88% of predicted (range, 39-125%). After 15+9 months of ERT, spirometry measurements were recorded in 15 patients. Decline in FEV1 was -2+5% of predicted. (p40.05, measured by the Wilcoxon signed-rank test). Median change in DLCO was -10% of predicted (-40 to +25%, p40.05). High resolution computed tomography scans demonstrated a moderate thickening of the bronchial wall in affected individuals, without evidence of emphysema. Conclusion: We conclude that Fabry disease can be complicated by significant airway obstruction, particularly in patients in the advanced stages of the disease, and that in the period studied, ERT had no demonstrable impact on pulmonary function.

Nedd4-2 ubiquitin ligase: a contributor to experimental neuropathic pain?

Background: Neuropathic pain is associated with altered expression of voltage-gated sodium channels (VGSCs) leading to peripheral nerve hyperexcitability. Interestingly, in cell expression systems, the ubiquitin ligase Nedd4-2 regulates the cell membrane density of the most abundant peripheral and pain-related VGSC, namely Nav1.7, and decreases its sodium current. Yet nothing is known about the involvement of Nedd4-2 in nociception and chronic pain. Therefore, the goal of this study is (i) to characterize Nedd4-2 and Nav1.7 expression in an experimental model of neuropathic pain (ii) to design by viral vector-mediated gene therapy an approach to depict the implication of Nedd4-2 in chronic pain. Methods: Western Blot and immunohistochemistry experiments detecting Nav1.7 and Nedd4-2 were performed in rodent DRGs 7 days after spared nerve injury (SNI). For the viral vector-mediated gene therapy, a recombinant Adeno-Associated Virus (rAAV2/6) was generated expressing the Nedd4-2 gene. Intrathecal injection of rAAV2/6 was followed 2 weeks after by the SNI surgery. Data are expressed in mean ± SEM, n = 4 in each condition. Results: Immunofluorescence on DRGs neurons reveals a decreased number of positive Nedd4-2 cells in the SNI model (27.0 ± 1.2%) versus sham group (43.4 ± 3.5%; p <0.005), as well as an increase in positive Nav1.7 cells in SNI (50.1 ± 2.9%) versus Sham (41.6 ± 1.8%; p <0.05). The change of Nedd4-2 expression was confirmed by western-blot analysis. In addition, we show that Nedd4-2 and Nav1.7 are largely expressed in overlapping cell populations, chiefly colocalizing with markers of small nociceptive neurons. Furthermore, we report that intrathecal injection of rAAV is able to counteract the reduction of Nedd4-2 expression in SNI animals. Conclusion: Our results indicate that Nedd4-2 is mainly expressed in nociceptors and downregulated after nerve injury. Moreover, our data suggest that the reduction of Nedd4-2, after nerve injury, may modulate Nav1.7 activity and contribute to hyperexcitability in neuropathic pain. A normal level of Nedd4-2 can be restored using a viral vector and we will further assess its functional effect on pain sensitivity.

Insulin resistance in adult cardiomyocytes undergoing dedifferentiation: role of GLUT4 expression and translocation.

Myocardium undergoing remodeling in vivo exhibits insulin resistance that has been attributed to a shift from the insulin-sensitive glucose transporter GLUT4 to the fetal, less insulin-sensitive, isoform GLUT1. To elucidate the role of altered GLUT4 expression in myocardial insulin resistance, glucose uptake and the expression of the glucose transporter isoforms GLUT4 and GLUT1 were measured in adult rat cardiomyocytes (ARC). ARC in culture spontaneously undergo dedifferentiation, hypertrophy-like spreading, and return to a fetal-like gene expression pattern. Insulin stimulation of 2-deoxy-D-glucose uptake was completely abolished on day 2 and 3 of culture and recovered thereafter. Although GLUT4 protein level was reduced, the time-course of unresponsiveness to insulin did not correlate with altered expression of GLUT1 and GLUT4. However, translocation of GLUT4 to the sarcolemma in response to insulin was completely abolished during transient insulin resistance. Insulin-mediated phosphorylation of Akt was not reduced, indicating that activation of phosphatidylinositol 3-kinase (PI3K) was preserved. On the other hand, total and phosphorylated Cbl was reduced during insulin resistance, suggesting that activation of Cbl/CAP is essential for insulin-mediated GLUT4 translocation, in addition to activation of PI3K. Pharmacological inhibition of contraction in insulin-sensitive ARC reduced insulin sensitivity and lowered phosphorylated Cbl. The results suggest that transient insulin resistance in ARC is related to impairment of GLUT4 translocation. A defect in the PI3K-independent insulin signaling pathway involving Cbl seems to contribute to reduced insulin responsiveness and may be related to contractile arrest.

Efficacy of enzyme replacement therapy in Fabry disease.

Enzyme replacement therapy has recently been introduced to treat Fabry disease, a rare X-linked lysosomal storage disorder. The disease occurs due to deficient activity of alpha-galactosidase A, leading to progressive accumulation of globotriaosylceramide in multiple organs and tissues. Renal, cardiac and cerebrovascular manifestations of the disease result in premature death in both hemizygous males and heterozygous females. This paper outlines the clinical signs, symptoms and diagnosis of Fabry disease, and the development of the two available enzyme replacement therapies -- agalsidase alfa and agalsidase beta. Agalsidase alfa and agalsidase beta are produced in a human cell line and in Chinese hamster ovary cells, respectively, resulting in products with the same amino acid sequence as the native human enzyme, but with different patterns of glycosylation. Correct post-translational glycosylation is important in terms of the pharmacokinetics, biodistribution, clinical efficacy and tolerability of genetically engineered protein therapeutics. Differences in glycosylation, which may affect immunogenicity and mannose-6-phosphate receptor-mediated cellular internalisation of administered enzyme, possibly account for the differences in dosing, clinical effects and safety profiles reported for agalsidase alfa and agalsidase beta.

Role of the ubiquitin system in regulating ion transport.

Ion channels and transporters play a critical role in ion and fluid homeostasis and thus in normal animal physiology and pathology. Tight regulation of these transmembrane proteins is therefore essential. In recent years, many studies have focused their attention on the role of the ubiquitin system in regulating ion channels and transporters, initialed by the discoveries of the role of this system in processing of Cystic Fibrosis Transmembrane Regulator (CFTR), and in regulating endocytosis of the epithelial Na(+) channel (ENaC) by the Nedd4 family of ubiquitin ligases (mainly Nedd4-2). In this review, we discuss the role of the ubiquitin system in ER Associated Degradation (ERAD) of ion channels, and in the regulation of endocytosis and lysosomal sorting of ion channels and transporters, focusing primarily in mammalian cells. We also briefly discuss the role of ubiquitin like molecules (such as SUMO) in such regulation, for which much less is known so far.

The ubiquitin-proteasome system in glioma cell cycle control.

A major determinant of cell fate is regulation of cell cycle. Tight regulation of this process is lost during the course of development and progression of various tumors. The ubiquitin-proteasome system (UPS) constitutes a universal protein degradation pathway, essential for the consistent recycling of a plethora of proteins with distinct structural and functional roles within the cell, including cell cycle regulation. High grade tumors, such as glioblastomas have an inherent potential of escaping cell cycle control mechanisms and are often refractory to conventional treatment. Here, we review the association of UPS with several UPS-targeted proteins and pathways involved in regulation of the cell cycle in malignant gliomas, and discuss the potential role of UPS inhibitors in reinstitution of cell cycle control.

The ubiquitin-like protein LC3 regulates the Rho-GEF activity of AKAP-Lbc.

AKAP-Lbc is a member of the A-kinase anchoring protein (AKAP) family that has been recently associated with the development of pathologies, such as cardiac hypertrophy and cancer. We have previously demonstrated that, at the molecular level, AKAP-Lbc functions as a guanine nucleotide exchange factor (GEF) that promotes the specific activation of RhoA. In the present study, we identified the ubiquitin-like protein LC3 as a novel regulatory protein interacting with AKAP-Lbc. Mutagenesis studies revealed that LC3, through its NH(2)-terminal alpha-helical domain, interacts with two binding sites located within the NH(2)-terminal regulatory region of AKAP-Lbc. Interestingly, LC3 overexpression strongly reduced the ability of AKAP-Lbc to interact with RhoA, profoundly impairing the Rho-GEF activity of the anchoring protein and, as a consequence, its ability to promote cytoskeletal rearrangements associated with the formation of actin stress fibers. Moreover, AKAP-Lbc mutants that fail to interact with LC3 show a higher basal Rho-GEF activity as compared with the wild type protein and become refractory to the inhibitory effect of LC3. This suggests that LC3 binding maintains AKAP-Lbc in an inactive state that displays a reduced ability to promote downstream signaling. Collectively, these findings provide evidence for a previously uncharacterized role of LC3 in the regulation of Rho signaling and in the reorganization of the actin cytoskeleton.

Regulation of Nav1.7 and Nav1.8 voltage-gated sodium channels by Nedd4-2 and β-subunits and its implication in neuropathic pain

In mammals, the presence of excitable cells in muscles, heart and nervous system is crucial and allows fast conduction of numerous biological information over long distances through the generation of action potentials (AP). Voltage-gated sodium channels (Navs) are key players in the generation and propagation of AP as they are responsible for the rising phase of the AP. Navs are heteromeric proteins composed of a large pore-forming a-subunit (Nav) and smaller ß-auxiliary subunits. There are ten genes encoding for Navl.l to Nav1.9 and NaX channels, each possessing its own specific biophysical properties. The excitable cells express differential combinations of Navs isoforms, generating a distinct electrophysiological signature. Noteworthy, only when anchored at the membrane are Navs functional and are participating in sodium conductance. In addition to the intrinsic properties of Navs, numerous regulatory proteins influence the sodium current. Some proteins will enhance stabilization of membrane Navs while others will favour internalization. Maintaining equilibrium between the two is of crucial importance for controlling cellular excitability. The E3 ubiquitin ligase Nedd4-2 is a well-characterized enzyme that negatively regulates the turnover of many membrane proteins including Navs. On the other hand, ß-subunits are known since long to stabilize Navs membrane anchoring. Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of Navs expressed in dorsal root ganglion (DRG) sensory neurons as highlighted in different animal models of neuropathic pain. Among Navs, Nav1.7 and Nav1.8 are abundantly and specifically expressed in DRG sensory neurons and have been recurrently incriminated in nociception and neuropathic pain development. Using the spared nerve injury (SNI) experimental model of neuropathic pain in mice, I observed a specific reduction of Nedd4-2 in DRG sensory neurons. This decrease subsequently led to an upregulation of Nav1.7 and Nav1.8 protein and current, in the axon and the DRG neurons, respectively, and was sufficient to generate neuropathic pain-associated hyperexcitability. Knocking out Nedd4-2 specifically in nociceptive neurons led to the same increase of Nav1.7 and Nav1.8 concomitantly with an increased thermal sensitivity in mice. Conversely, rescuing Nedd4-2 downregulation using viral vector transfer attenuated neuropathic pain mechanical hypersensitivity. This study demonstrates the significant role of Nedd4-2 in regulating cellular excitability in vivo and its involvement in neuropathic pain development. The role of ß-subunits in neuropathic pain was already demonstrated in our research group. Because of their stabilization role, the increase of ßl, ß2 and ß3 subunits in DRGs after SNI led to increased Navs anchored at the membrane. Here, I report a novel mechanism of regulation of a-subunits by ß- subunits in vitro; ßl and ß3-subunits modulate the glycosylation pattern of Nav1.7, which might account for stabilization of its membrane expression. This opens new perspectives for investigation Navs state of glycosylation in ß-subunits dependent diseases, such as in neuropathic pain. - Chez les mammifères, la présence de cellules excitables dans les muscles, le coeur et le système nerveux est cruciale; elle permet la conduction rapide de nombreuses informations sur de longues distances grâce à la génération de potentiels d'action (PA). Les canaux sodiques voltage-dépendants (Navs) sont des participants importants dans la génération et la propagation des PA car ils sont responsables de la phase initiale de dépolarisation du PA. Les Navs sont des protéines hétéromériques composées d'une grande sous-unité a (formant le pore du canal) et de petites sous-unités ß accompagnatrices. Il existe dix gènes qui codent pour les canaux sodiques, du Nav 1.1 au Nav 1.9 ainsi que NaX, chacun possédant des propriétés biophysiques spécifiques. Les cellules excitables expriment différentes combinaisons des différents isoformes de Navs, qui engendrent une signature électrophysiologique distincte. Les Navs ne sont fonctionnels et ne participent à la conductibilité du Na+, que s'ils sont ancrés à la membrane plasmique. En plus des propriétés intrinsèques des Navs, de nombreuses protéines régulatrices influencent également le courant sodique. Certaines protéines vont favoriser l'ancrage et la stabilisation des Navs exprimés à la membrane, alors que d'autres vont plutôt favoriser leur internalisation. Maintenir l'équilibre des deux processus est crucial pour contrôler l'excitabilité cellulaire. Dans ce contexte, Nedd4-2, de la famille des E3 ubiquitin ligase, est une enzyme bien caractérisée qui régule l'internalisation de nombreuses protéines, notamment celle des Navs. Inversement, les sous-unités ß sont connues depuis longtemps pour stabiliser l'ancrage des Navs à la membrane. La douleur neuropathique périphérique est une condition débilitante résultant d'une atteinte à un nerf. Elle est caractérisée par la dérégulation des Navs exprimés dans les neurones sensoriels du ganglion spinal (DRG). Ceci a été démontré à de multiples occasions dans divers modèles animaux de douleur neuropathique. Parmi les Navs, Nav1.7 et Nav1.8 sont abondamment et spécifiquement exprimés dans les neurones sensoriels des DRG et ont été impliqués de façon récurrente dans le développement de la douleur neuropathique. En utilisant le modèle animal de douleur neuropathique d'épargne du nerf sural (spared nerve injury, SNI) chez la souris, j'ai observé une réduction spécifique des Nedd4-2 dans les neurones sensoriels du DRG. Cette diminution avait pour conséquence l'augmentation de l'expression des protéines et des courants de Nav 1.7 et Nav 1.8, respectivement dans l'axone et les neurones du DRG, et était donc suffisante pour créer l'hyperexcitabilité associée à la douleur neuropathique. L'invalidation pour le gène codant pour Nedd4-2 dans une lignée de souris génétiquement modifiées a conduit à de similaires augmentations de Nav1.7 et Nav1.8, parallèlement à une augmentation à la sensibilité thermique. A l'opposé, rétablir une expression normale de Nedd4-2 en utilisant un vecteur viral a eu pour effet de contrecarrer le développement de l'hypersensibilité mécanique lié à ce modèle de douleur neuropathique. Cette étude démontre le rôle important de Nedd4-2 dans la régulation de l'excitabilité cellulaire in vivo et son implication dans le développement des douleurs neuropathiques. Le rôle des sous-unités ß dans les douleurs neuropathiques a déjà été démontré dans notre groupe de recherche. A cause de leur rôle stabilisateur, l'augmentation des sous-unités ßl, ß2 et ß3 dans les DRG après SNI, conduit à une augmentation des Navs ancrés à la membrane. Dans mon travail de thèse, j'ai observé un nouveau mécanisme de régulation des sous-unités a par les sous-unités ß in vitro. Les sous-unités ßl et ß3 régulent l'état de glycosylation du canal Nav1.7, et stabilisent son expression membranaire. Ceci ouvre de nouvelles perspectives dans l'investigation de l'état de glycosylation des Navs dans des maladies impliquant les sous-unités ß, notamment les douleurs neuropathiques.