Mambalgin-1 pain-relieving peptide locks the hinge between α4 and α5 helices to inhibit rat acid-sensing ion channel 1a

Salinas, Miguel; Kessler, Pascal; Douguet, Dominique; Sarraf, Daad; Tonali, Nicolò; Thaï, Robert; Servent, Denis; Lingueglia, Éric

doi:10.1016/j.neuropharm.2021.108453

Cited by 14 publications

(22 citation statements)

References 32 publications

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“…Notably, the mode of the α7-nAChR/SLURP-1 interaction differs from that found for other Ly6/uPAR proteins and their targets. For example, the region of loop II was found to be important for interaction of mambalgins with the acid sensitive ion channel ASIC1 ( Salinas et al, 2021 ), for fasciculins with acetylcholinesterase ( Falkenstein and Pena, 1997 ), for α-cobratoxin with the GABA A receptor ( Kudryavtsev et al, 2015 ), as well as for human neuromodulator Ly6/neurotoxin 1 (Lynx1) with α7-nAChR ( Lyukmanova et al, 2013 ). Loop II frequently contains almost all the determinants necessary for efficient interaction of snake α-neurotoxins with the nicotinic receptors ( Lyukmanova et al, 2007 , 2016b ; Rahman et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer

Bychkov

Shulepko

Shlepova

et al. 2021

Front. Cell Dev. Biol.

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Secreted Ly6/uPAR-related protein 1 (SLURP-1) is a secreted Ly6/uPAR protein that negatively modulates the nicotinic acetylcholine receptor of α7 type (α7-nAChR), participating in control of cancer cell growth. Previously we showed, that a recombinant analogue of human SLURP-1 (rSLURP-1) diminishes the lung adenocarcinoma A549 cell proliferation and abolishes the nicotine-induced growth stimulation. Here, using multiplex immunoassay, we demonstrated a decrease in PTEN and mammalian target of rapamycin (mTOR) kinase phosphorylation in A549 cells upon the rSLURP-1 treatment pointing on down-regulation of the PI3K/AKT/mTOR signaling pathway. Decreased phosphorylation of the platelet-derived growth factor receptor type β (PDGFRβ) and arrest of the A549 cell cycle in the S and G2/M phases without apoptosis induction was also observed. Using a scratch migration assay, inhibition of A549 cell migration under the rSLURP-1 treatment was found. Affinity extraction demonstrated that rSLURP-1 in A549 cells forms a complex not only with α7-nAChR, but also with PDGFRα and epidermal growth factor receptor (EGFR), which are known to be involved in regulation of cancer cell growth and migration and are able to form a heterodimer. Knock-down of the genes encoding α7-nAChR, PDGFRα, and EGFR confirmed the involvement of these receptors in the anti-migration effect of SLURP-1. Thus, SLURP-1 can target the α7-nAChR complexes with PDGFRα and EGFR in the membrane of epithelial cells. Using chimeric proteins with grafted SLURP-1 loops we demonstrated that loop I is the principal active site responsible for the SLURP-1 interaction with α7-nAChR and its antiproliferative effect. Synthetic peptide mimicking the loop I cyclized by a disulfide bond inhibited ACh-evoked current at α7-nAChR, as well as A549 cell proliferation and migration. This synthetic peptide represents a promising prototype of new antitumor drug with the properties close to that of the native SLURP-1 protein.

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Section: Discussionmentioning

confidence: 99%

SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer

Bychkov

Shulepko

Shlepova

et al. 2021

Front. Cell Dev. Biol.

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“…Because TFPs usually contain 4 to 5 pairs of disulfide bonds, it is usually very hard to recombinantly express them, and those commercially available are mostly purified from snake venoms. Some researchers used chemical synthesis that successfully obtained these rTFPs, such as mambalgin-1 and mambalgin-2 (Diochot et al, 2012; Mourier et al, 2016; Pan et al, 2014; Salinas et al, 2021; Schroeder et al, 2014; Sun et al, 2018). However, due to the high cost in chemical synthesis and limited yields, these successful attempts did not change the overall scenario for production of other TFPs.…”

Section: Discussionmentioning

confidence: 99%

“…Ophiophagus hannah NOS activator α2βγε nAChR blocker 5 No (Pu et al, 1995a(Pu et al, , 1995b Mambalgin-1 Dendroaspis polylepis ASIC1a blocker 4 Yes (Diochot et al, 2012;Mourier et al, 2016;Salinas et al, 2021Salinas et al, , 2014Sun et al, 2018) MTa Dendrosaspis angusticeps a2B-adrenoceptor blocker 4 No (Koivula et al, 2010) αCTX Naja kaouthia α2βγε nAChR blocker 5 Yes (Betzel et al, 1991;Karlsson and Eaker, 1972) mouse Pate B Mouse phosphatidylethanolamine phosphatidylserine?…”

Section: Hannalgesinmentioning

confidence: 99%

Scalable production of recombinant three-finger proteins: from inclusion bodies to high quality molecular probes

Lei

et al. 2022

Preprint

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We introduce a working pipeline for expression, purification and validation of disulfide- bond rich three-finger proteins using E. coli as the expression host. With this pipeline, we have successfully obtained highly purified and bioactive recombinant α-Βungarotoxin, k- Bungarotoxin, Hannalgesin, Mambalgin-1, α-Cobratoxin, MTα, Slurp1, Pate B etc. Milligrams to hundreds of milligrams of recombinant three finger proteins were obtained within weeks in the lab. The recombinant proteins showed specificity in binding assay and six of them were crystallized and structurally validated using X-ray diffraction protein crystallography. As many three finger proteins have attractive therapeutic or research interests and due to the extremely high quality of the recombinant three finger proteins we obtained, our method provides a competitive alternative to either their native counterparts or chemically synthetic ones, and should facilitate related research and applications.

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“…Other animal toxins that have exhibited inhibitory properties of ASICs are mambalgins [120][121][122][123][124][125]. As a toxin derived from the venom of Dendroaspis polylepis [120], mambalgins are classified into three subtypes (mambalgin-1, -2, -3) which function similarly to inhibit all ASIC subunit combinations such as heteromeric ASIC1a/2a but not individual ASIC2a [120].…”

Section: Mambalginsmentioning

confidence: 99%

Acid-Sensing Ion Channel 2: Function and Modulation

et al. 2022

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Acid-sensing ion channels (ASICs) have an important influence on human physiology and pathology. They are members of the degenerin/epithelial sodium channel family. Four genes encode at least six subunits, which combine to form a variety of homotrimers and heterotrimers. Of these, ASIC1a homotrimers and ASIC1a/2 heterotrimers are most widely expressed in the central nervous system (CNS). Investigations into the function of ASIC1a in the CNS have revealed a wealth of information, culminating in multiple contemporary reviews. The lesser-studied ASIC2 subunits are in need of examination. This review will focus on ASIC2 in health and disease, with discussions of its role in modulating ASIC function, synaptic targeting, cardiovascular responses, and pharmacology, while exploring evidence of its influence in pathologies such as ischemic brain injury, multiple sclerosis, epilepsy, migraines, drug addiction, etc. This information substantiates the ASIC2 protein as a potential therapeutic target for various neurological, psychological, and cerebrovascular diseases.

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Mambalgin-1 pain-relieving peptide locks the hinge between α4 and α5 helices to inhibit rat acid-sensing ion channel 1a

Cited by 14 publications

References 32 publications

SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer

SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer

Scalable production of recombinant three-finger proteins: from inclusion bodies to high quality molecular probes

Acid-Sensing Ion Channel 2: Function and Modulation

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