scholarly journals Multiple Kv Channel-interacting Proteins Contain an N-terminal Transmembrane Domain That Regulates Kv4 Channel Trafficking and Gating

2008 ◽  
Vol 283 (51) ◽  
pp. 36046-36059 ◽  
Author(s):  
Henry H. Jerng ◽  
Paul J. Pfaffinger
Keyword(s):  
Transmembrane Domain ◽  
Interacting Proteins ◽  
Channel Trafficking ◽  
Kv Channel

scholarly journals Carbamazepine as a Novel Small Molecule Corrector of Trafficking-impaired ATP-sensitive Potassium Channels Identified in Congenital Hyperinsulinism

2013 ◽  
Vol 288 (29) ◽  
pp. 20942-20954 ◽  
Author(s):  
Pei-Chun Chen ◽  
Erik M. Olson ◽  
Qing Zhou ◽  
Yelena Kryukova ◽  
Heidi M. Sampson ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Misfolding ◽  
Secretory Pathway ◽  
Transmembrane Domain ◽  
Congenital Hyperinsulinism ◽  
Sulfonylurea Receptor ◽  
Channel Activity ◽  
Channel Trafficking ◽  
Channel Function ◽  
Trafficking Defects

ATP-sensitive potassium (KATP) channels consisting of sulfonylurea receptor 1 (SUR1) and the potassium channel Kir6.2 play a key role in insulin secretion by coupling metabolic signals to β-cell membrane potential. Mutations in SUR1 and Kir6.2 that impair channel trafficking to the cell surface lead to loss of channel function and congenital hyperinsulinism. We report that carbamazepine, an anticonvulsant, corrects the trafficking defects of mutant KATP channels previously identified in congenital hyperinsulinism. Strikingly, of the 19 SUR1 mutations examined, only those located in the first transmembrane domain of SUR1 responded to the drug. We show that unlike that reported for several other protein misfolding diseases, carbamazepine did not correct KATP channel trafficking defects by activating autophagy; rather, it directly improved the biogenesis efficiency of mutant channels along the secretory pathway. In addition to its effect on channel trafficking, carbamazepine also inhibited KATP channel activity. Upon subsequent removal of carbamazepine, however, the function of rescued channels was recovered. Importantly, combination of the KATP channel opener diazoxide and carbamazepine led to enhanced mutant channel function without carbamazepine washout. The corrector effect of carbamazepine on mutant KATP channels was also demonstrated in rat and human β-cells with an accompanying increase in channel activity. Our findings identify carbamazepine as a novel small molecule corrector that may be used to restore KATP channel expression and function in a subset of congenital hyperinsulinism patients.

scholarly journals Novel ORAI1 Mutation Disrupts Channel Trafficking Resulting in Combined Immunodeficiency

2021 ◽  
Author(s):  
Fang Yu ◽  
Nourhen Agrebi ◽  
Rafah Mackeh ◽  
Khaled Abouhazima ◽  
Khadija KhudaBakhsh ◽  
...  
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Transmembrane Domain ◽  
Recessive Mutation ◽  
Combined Immunodeficiency ◽  
Loss Of Function ◽  
Channel Trafficking ◽  
Positive Side ◽  
Anhidrotic Ectodermal Dysplasia ◽  
Functional Analyses

AbstractStore-operated Ca2+ entry (SOCE) represents a predominant Ca2+ influx pathway in non-excitable cells. SOCE is required for immune cell activation and is mediated by the plasma membrane (PM) channel ORAI1 and the endoplasmic reticulum (ER) Ca2+ sensor STIM1. Mutations in the Orai1 or STIM1 genes abolish SOCE leading to combined immunodeficiency (CID), muscular hypotonia, and anhidrotic ectodermal dysplasia. Here, we identify a novel autosomal recessive mutation in ORAI1 in a child with CID. The patient is homozygous for p.C126R mutation in the second transmembrane domain (TM2) of ORAI1, a region with no previous loss-of-function mutations. SOCE is suppressed in the patient’s lymphocytes, which is associated with impaired T cell proliferation and cytokine production. Functional analyses demonstrate that the p.C126R mutation does not alter protein expression but disrupts ORAI1 trafficking. Orai1-C126R does not insert properly into the bilayer resulting in ER retention. Insertion of an Arg on the opposite face of TM2 (L135R) also results in defective folding and trafficking. We conclude that positive side chains within ORAI1 TM2 are not tolerated and result in misfolding, defective bilayer insertion, and channel trafficking thus abolishing SOCE and resulting in CID.

scholarly journals FIT2 organizes lipid droplet biogenesis with ER tubule-forming proteins and septins

2021 ◽  
Vol 220 (5) ◽  
Author(s):  
Fang Chen ◽  
Bing Yan ◽  
Jie Ren ◽  
Rui Lyu ◽  
Yanfang Wu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Oleic Acid ◽  
Energy Metabolism ◽  
Molecular Basis ◽  
Lipid Droplets ◽  
Adipocyte Differentiation ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Cytoskeletal Protein ◽  
Interacting Proteins

Lipid droplets (LDs) are critical for lipid storage and energy metabolism. LDs form in the endoplasmic reticulum (ER). However, the molecular basis for LD biogenesis remains elusive. Here, we show that fat storage–inducing transmembrane protein 2 (FIT2) interacts with ER tubule-forming proteins Rtn4 and REEP5. The association is mainly transmembrane domain based and stimulated by oleic acid. Depletion of ER tubule-forming proteins decreases the number and size of LDs in cells and Caenorhabditis elegans, mimicking loss of FIT2. Through cytosolic loops, FIT2 binds to cytoskeletal protein septin 7, an interaction that is also required for normal LD biogenesis. Depletion of ER tubule-forming proteins or septins delays nascent LD formation. In addition, FIT2-interacting proteins are up-regulated during adipocyte differentiation, and ER tubule-forming proteins, septin 7, and FIT2 are transiently enriched at LD formation sites. Thus, FIT2-mediated nascent LD biogenesis is facilitated by ER tubule-forming proteins and septins.

scholarly journals Disease Associated Mutations in KIR Proteins Linked to Aberrant Inward Rectifier Channel Trafficking

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 650 ◽  
Author(s):  
Eva-Maria Zangerl-Plessl ◽  
Muge Qile ◽  
Meye Bloothooft ◽  
Anna Stary-Weinzinger ◽  
Marcel A. G. van der Heyden
Keyword(s):  
Transmembrane Domain ◽  
Neural System ◽  
Inward Rectifier ◽  
Channel Trafficking ◽  
Kir Channels ◽  
Cellular Processes ◽  
Er Retention ◽  
Organ Systems ◽  
Mutational Hotspots ◽  
Channel Expression

The ubiquitously expressed family of inward rectifier potassium (KIR) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Channel mutations associate with a variety of severe human diseases and syndromes, affecting many organ systems including the central and peripheral neural system, heart, kidney, pancreas, and skeletal muscle. A number of mutations associate with altered ion channel expression at the plasma membrane, which might result from defective channel trafficking. Trafficking involves cellular processes that transport ion channels to and from their place of function. By alignment of all KIR channels, and depicting the trafficking associated mutations, three mutational hotspots were identified. One localized in the transmembrane-domain 1 and immediately adjacent sequences, one was found in the G-loop and Golgi-export domain, and the third one was detected at the immunoglobulin-like domain. Surprisingly, only few mutations were observed in experimentally determined Endoplasmic Reticulum (ER)exit-, export-, or ER-retention motifs. Structural mapping of the trafficking defect causing mutations provided a 3D framework, which indicates that trafficking deficient mutations form clusters. These “mutation clusters” affect trafficking by different mechanisms, including protein stability.

scholarly journals Kv2.1 Cell Surface Clusters are Insertion and Retrieval Platforms For Kv Channel Trafficking at the Plasma Membrane

2012 ◽  
Vol 102 (3) ◽  
pp. 105a-106a
Author(s):  
Philip D. Fox ◽  
Aubrey V. Weigel ◽  
Emily Deutsch ◽  
Elizabeth J. Akin ◽  
Gentry Hansen ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Channel Trafficking ◽  
Kv Channel

scholarly journals Functional features of the “finger” domain of the DEG/ENaC channels MEC-4 and UNC-8

2018 ◽  
Vol 315 (2) ◽  
pp. C155-C163 ◽  
Author(s):  
Cristina Matthewman ◽  
Christina K. Johnson ◽  
David M. Miller ◽  
Laura Bianchi
Keyword(s):  
Neuronal Death ◽  
Transmembrane Domain ◽  
Divalent Cations ◽  
Channel Trafficking ◽  
Chaperone Protein ◽  
Unique Manner ◽  
Functional Features ◽  
And Function ◽  
High Degree

UNC-8 and MEC-4 are two members of the degenerin/epithelial Na+ channel (DEG/ENaC) family of voltage-independent Na+ channels that share a high degree of sequence homology and functional similarity. For example, both can be hyperactivated by genetic mutations [UNC-8(d) and MEC-4(d)] that induce neuronal death by necrosis. Both depend in vivo on chaperone protein MEC-6 for function, as demonstrated by the finding that neuronal death induced by hyperactive UNC-8 and MEC-4 channels is prevented by null mutations in mec-6. UNC-8 and MEC-4 differ functionally in three major ways: 1) MEC-4 is calcium permeable, whereas UNC-8 is not; 2) UNC-8, but not MEC-4, is blocked by extracellular calcium and magnesium in the micromolar range; and 3) MEC-6 increases the number of MEC-4 channels at the cell surface in oocytes but does not have this effect on UNC-8. We previously reported that Ca2+permeability of MEC-4 is conferred by the second transmembrane domain. We show here that the extracellular “finger” domain of UNC-8 is sufficient to mediate inhibition by divalent cations and that regulation by MEC-6 also depends on this region. Thus, our work confirms that the finger domain houses residues involved in gating of this channel class and shows for the first time that the finger domain also mediates regulation by chaperone protein MEC-6. Given that the finger domain is the most divergent region across the DEG/ENaC family, we speculate that it influences channel trafficking and function in a unique manner depending on the channel subunit.

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