Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

Wong, Adrian Y. C.; Hristova, Elitza; Ahlskog, Nina; Tassé, Louis-Alexandre; Ngsee, Johnny K.; Chudalayandi, Prakash; Bergeron, Richard

doi:10.1124/mol.116.104018

Cited by 27 publications

(37 citation statements)

References 87 publications

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“…; Wong et al. ). In this work, we show that Sig‐1R activation by SKF inhibits Kv1.2, as observed for other Kv1.x subtypes (Aydar et al.…”

Section: Discussionmentioning

confidence: 98%

“…, , ; Wong et al. ). Additionally, it has been shown that the Sig‐1R can translocate to the nuclear envelope upon activation with cocaine, and it has also been reported that the Sig‐1R may reside in the PM in dorsal root ganglion (DRG) neurons (Mavlyutov et al.…”

Section: Discussionmentioning

confidence: 99%

“…All traces were post hoc leak‐subtracted prior to analysis using a 1/10 step protocol as previously described (Wong et al. ).…”

Section: Methodsmentioning

confidence: 99%

“…; Wong et al. ). Sig‐1R seems to meet all the criteria as an auxiliary subunit for Kv1.x channels, as it can modulate Kv1.x biophysical properties (Aydar et al.…”

Section: Introductionmentioning

confidence: 98%

“…The Sig-1R is an endoplasmic reticulum (ER)-resident protein that translocates to other cellular compartments, including the plasma membrane, upon ligand activation (Su et al 2010;Kourrich 2017), and modulates a plethora of potassium channels (Soriani et al 1999;Wilke et al 1999;Lupardus et al 2000;Aydar et al 2002;Zhang and Cuevas 2005;Martina et al 2007;Kinoshita et al 2012;Wong et al 2016). Sig-1R seems to meet all the criteria as an auxiliary subunit for Kv1.x channels, as it can modulate Kv1.x biophysical properties (Aydar et al 2002;Kinoshita et al 2012), and facilitates Kv1.x trafficking to the plasma membrane (Kourrich et al 2013;Delint-Ramirez et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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The sigma‐1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells

et al. 2019

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Expression of Kv1.2 within Kv1.x potassium channel complexes is critical in maintaining appropriate neuronal excitability and determining the threshold for action potential firing. This is attributed to the interaction of Kv1.2 with a hitherto unidentified protein that confers bimodal channel activation gating, allowing neurons to adapt to repetitive trains of stimulation and protecting against hyperexcitability. One potential protein candidate is the sigma‐1 receptor (Sig‐1R), which regulates other members of the Kv1.x channel family; however, the biophysical nature of the interaction between Sig‐1R and Kv1.2 has not been elucidated. We hypothesized that Sig‐1R may regulate Kv1.2 and may further act as the unidentified modulator of Kv1.2 activation. In transiently transfected HEK 293 cells, we found that ligand activation of the Sig‐1R modulates Kv1.2 current amplitude. More importantly, Sig‐1R interacts with Kv1.2 in baseline conditions to influence bimodal activation gating. These effects are abolished in the presence of the auxiliary subunit Kv β 2 and when the Sig‐1R mutation underlying ALS 16 (Sig‐1R‐E102Q), is expressed. These data suggest that Kv β 2 occludes the interaction of Sig‐1R with Kv1.2, and that E102 may be a residue critical for Sig‐1R modulation of Kv1.2. The results of this investigation describe an important new role for Sig‐1R in the regulation of neuronal excitability and introduce a novel mechanism of pathophysiology in Sig‐1R dysfunction.

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“…; Wong et al. ). In this work, we show that Sig‐1R activation by SKF inhibits Kv1.2, as observed for other Kv1.x subtypes (Aydar et al.…”

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

“…All traces were post hoc leak‐subtracted prior to analysis using a 1/10 step protocol as previously described (Wong et al. ).…”

Section: Methodsmentioning

confidence: 99%

“…; Wong et al. ). Sig‐1R seems to meet all the criteria as an auxiliary subunit for Kv1.x channels, as it can modulate Kv1.x biophysical properties (Aydar et al.…”

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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The sigma‐1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells

et al. 2019

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Structural Perspectives on Sigma-1 Receptor Function

Alon

Schmidt

Zheng

et al. 2017

Advances in Experimental Medicine and Biology

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The sigma-1 receptor is an enigmatic ER-resident transmembrane protein linked to a variety of human diseases. Although the receptor was first cloned 20 years ago, the molecular structure of the protein and the mechanistic basis for its interaction with drug-like small molecules have remained unclear until recently. The determination of the first crystal structure of human sigma-1 offered the first detailed views of the sigma-1 architecture, and revealed an unusual overall fold with a single transmembrane helix in each protomer. The structure shows an overall trimeric receptor arrangement, and each protomer binds a single ligand molecule at the center of its carboxy-terminal domain. These results offer detailed molecular views of receptor structure, oligomerization, and ligand recognition, providing a framework for the next era of sigma-1 research.

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Sigma 1 Receptor and Ion Channel Dynamics in Cancer

Soriani

Rapetti-Mauss

2017

Advances in Experimental Medicine and Biology

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SigmaR1 is a multitasking chaperone protein which has mainly been studied in CNS physiological and pathophysiological processes such as pain, memory, neurodegenerative diseases (amyotrophic lateral sclerosis , Parkinson's and Alzheimer's diseases, retinal neurodegeneration ), stroke and addiction . Strikingly, G-protein and ion channels are the main client protein fami lies of this atypical chaperone and the recent advances that have been performed for the last 10 years demonstrate that SigmaR1 is principally activated following tissue injury and disease development to promote cell survival. In this chapter, we synthesize the data enhancing our comprehension of the interaction between SigmaR1 and ion channels and the unexpected consequences of such functional coupling in cancer development. We also describe a model in which the pro-survival functions of SigmaR1 observed in CNS pathologies are hijacked by cancer cells to shape their electrical signature and behavior in response to the tumor microenvironment .

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Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

Cited by 27 publications

References 87 publications

The sigma‐1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells

The sigma‐1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells

Structural Perspectives on Sigma-1 Receptor Function

Sigma 1 Receptor and Ion Channel Dynamics in Cancer

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