Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1

Er, Sing Yan; Cristofori-Armstrong, Ben; Escoubas, Pierre; Rash, Lachlan D.

doi:10.1016/j.neuropharm.2017.03.020

Cited by 29 publications

(24 citation statements)

References 57 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Testing of these mutants for sensitivity to PcTx1 identified Arg175 and Glu177 (Cys and Gly in ASIC1b, respectively) to play a key role in the subtype dependent effects of Hm3a. Er et al also showed that Hm3a potentiates acid-induced currents in oocytes co-injected with rASIC1a and rASIC1b (Er et al, 2017), an effect we observed for PcTx1 (unpublished observations), which has not previously been noted.…”

Section: Hm3asupporting

confidence: 76%

“…However, it remained unstudied and unreported until now. In this issue of Neuropharmacology we present the characterisation of π-TRTX-Hm3a (Hm3a) isolated from the Togo starburst tarantula (Heteroscodra maculata) (Er et al, 2017). Hm3a has five amino acid substitutions compared to PcTx1 and is shorter by three residues at the C-terminus (Figure 2A).…”

Section: Hm3amentioning

confidence: 99%

See 1 more Smart Citation

Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms

Cristofori-Armstrong

Rash

2017

Neuropharmacology

Self Cite

View full text Add to dashboard Cite

Please cite this article as: Cristofori-Armstrong, B., Rash, L.D., Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms, Neuropharmacology (2017), doi: 10.1016/j.neuropharm.2017.04.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT2 ABSTRACT Acid-sensing ion channels (ASICs) are proton-activated cation channels that are expressed in a variety of neuronal and non-neuronal tissues. As proton-gated channels, they have been implicated in many pathophysiological conditions where pH is perturbed. Venom derived compounds represent the most potent and selective modulators of ASICs described to date, and thus have been invaluable as pharmacological tools to study ASIC structure, function, and biological roles. There are now ten ASIC modulators described from animal venoms, with those from snakes and spiders favouring ASIC1, while the sea anemones preferentially target ASIC3. Some modulators, such as the prototypical ASIC1 modulator PcTx1 have been studied in great detail, while some of the newer members of the club remain largely unstudied. Here we review the current state of knowledge on venom derived ASIC modulators, with a particular focus on their molecular interaction with ASICs, what they have taught us about channel structure, and what they might still reveal about ASIC function and pathophysiological roles.

show abstract

Section: Hm3asupporting

confidence: 76%

Section: Hm3amentioning

confidence: 99%

Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms

Cristofori-Armstrong

Rash

2017

Neuropharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Despite its high sequence similarity with PcTx1, Hm3a showed higher levels of stability over 48 hr. Overall, Hm3a represents a potent, highly stable tool for long term in vitro and in vivo experiments (Er, Cristofori-Armstrong, Escoubas, & Rash, 2017).…”

Section: Polypeptide Modulatorsmentioning

confidence: 99%

Synaptic signals mediated by protons and acid‐sensing ion channels

Uchitel

Inchauspe

Weissmann

2019

Synapse

View full text Add to dashboard Cite

Extracellular pH changes may constitute significant signals for neuronal communication. During synaptic transmission, changes in pH in the synaptic cleft take place. Its role in the regulation of presynaptic Ca2+ currents through multivesicular release in ribbon‐type synapses is a proven phenomenon. In recent years, protons have been recognized as neurotransmitters that participate in neuronal communication in synapses of several regions of the CNS such as amygdala, nucleus accumbens, and brainstem. Protons are released by nerve stimulation and activate postsynaptic acid‐sensing ion channels (ASICs). Several types of ASIC channels are expressed in the peripheral and central nervous system. The influx of Ca2+ through some subtypes of ASICs, as a result of synaptic transmission, agrees with the participation of ASICs in synaptic plasticity. Pharmacological and genetical inhibition of ASIC1a results in alterations in learning, memory, and phenomena like fear and cocaine‐seeking behavior. The recognition of endogenous molecules, such as arachidonic acid, cytokines, histamine, spermine, lactate, and neuropeptides, capable of inhibiting or potentiating ASICs suggests the existence of mechanisms of synaptic modulation that have not yet been fully identified and that could be tuned by new emerging pharmacological compounds with potential therapeutic benefits.

show abstract

“…These oxins have been ins rumen al o s udy he s ruc ure, properties, functional expression in above-mentioned physiopa hological s a es. Hcr1b-1 and Hm3a bo h are peptide oxins similar o PcrTx1 are ob ained from spider, snake and sea anemone venoms argeting for ASICs [59][60]. Dendro oxins (DTx) are a group of peptide oxins purified from he venom of several mamba snakes and α-DTx selectivi y and i s po ential in eraction wi h ASICs should be aken in consideration for inhibiting ASICs induced curren [61].…”

Section: Pharmacological Agents Availablementioning

confidence: 99%

Acid Sensing Ion Channels (Asics): Potential Targets for the Discovery of Novel Therapeutics in Disease Management

Roy¹

2018

IJCBR

View full text Add to dashboard Cite

INTRODUCTIONThe acid-sensing ion channels or ASICs form a distinc branch of he degenerin superfamily (ENaC/DEG) of sodium channels. A leas four ASIC genes have been identified in humans so far, numbered 1-4, wi h a number of splice varian s encoding a o al of nine unique pro eins [1][2][3][4][5][6][7][8][9]. The channels formed by he ASIC pro eins are basically pro on-ga ed cation channels, opening rapidly in he presence of ex racellular acid. All ASIC subuni consis s of a large ex racellular domain, 2 ransmembrane helices, and shor cy oplasmic N and C ermini. Functional ASICs are homo or he ero rimers of ASIC1a, ASIC1bASIC2a, ASIC2b, and/ or ASIC3 subuni s [10][11]. ASIC2b is no functional as homomultimer bu form functional he eromeric channels in combination wi h o her subuni s [12]. The activi y of ASIC4 channel has been de ec ed very limi ed ye . I may participa e in regulating he membrane availabili y of o her ASIC subuni s [13]. ASIC1a and ASIC3 are activa ed by an acidi y range (pH 7.0-6.0) observed in several acu e and chronic pain conditions. ASIC3 is particularly sensitive o lactic acidosis and hus is considered o be an impor an componen of acid induced pain [14].Corresponding author: Debendra Nath Roy, Department of Pharmacy, Faculty of Biological Science and Technology, Jessore University of Science and Technology, Jessore-7408, Bangladesh. Email: roydn009@gmail.com I has been noticed ha he activation of ASIC in neurons induce action po entials. The ex en and duration of he ASIC-media ed depolarization depends bo h on ASIC ampli ude activi y and he number of charges he channels ranspor during heir opening [15][16]. Among all o hers, ASIC3 is he mos sensitive o increases in pro on concen ration, wi h half-maximal pH activation is 6.4 [17]. ASIC2 is he leas sensitive, requiring exposure o pH 4.5 for halfmaximal activation. ASICs have been de ec ed hroughou he nervous sys em, specifically in areas of high synaptic densi y, localizing primarily o he soma and processes of neurons [18][19]. Their expression pattern has sugges ed ha hese channels play a role in sensory perception and various neural processes [20][21]. ASICs have widespread dis ribution o many regions in he nervous sys em including dorsal roo ganglia, cor ex, hippocampus, basal ganglia, amygdale, olfac ory bulb, cerebrum and elsewhere [22 -24]. In erestingly, ASICs are increasingly being de eced in nonneuronal settings including cancer cells [25], bone [26], in estinal and bladder epi helium cells and smoo h muscle [27][28][29][30]. Because ASICs are permeable o Na+, heir activation leads o membrane depolarization, hus inducing action po entials in neurons ASICs often have an activation effec on neurons. A s rong ASIC-media ed depolarization, however, can inhibi an already actively signaling neuron. ASIC1a has a small permeabili y for Ca2+ in addition o i s Na+ permeabili y, and some of i s cellular functions, as for example neurodegeneration after ischem- ABSTRACTAcid sensing ion channels (ASIC) are Na+ channels activa ed by ex ernal pro o...

show abstract

Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1

Cited by 29 publications

References 57 publications

Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms

Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms

Synaptic signals mediated by protons and acid‐sensing ion channels

Acid Sensing Ion Channels (Asics): Potential Targets for the Discovery of Novel Therapeutics in Disease Management

Contact Info

Product

Resources

About