Pharmacology of acid-sensing ion channels – Physiological and therapeutical perspectives

Baron, Anne; Lingueglia, Éric

doi:10.1016/j.neuropharm.2015.01.005

Cited by 135 publications

(150 citation statements)

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“…5 models and biophysical properties (Gründer and Pusch, 2015) of ASICs, and more comprehensive coverage of the in vivo use of ASIC modulating venom peptides to study the pathological roles of ASICs (Baron et al, 2013;Baron and Lingueglia, 2015).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…Being the first-discovered, selective inhibitor of ASICs, PcTx1 has been extensively used in animals to help determine the role of ASIC1a in a wide variety of physiological and pathological processes such as pain, anxiety, depression, epilepsy (with contrasting results) and respiratory control (Baron et al, 2013;Baron and Lingueglia, 2015;Wemmie et al, 2006;Wemmie et al, 2013). However, the standout condition in which PcTx1 has played a role in validating ASIC1a as a promising therapeutic target is ischaemic stroke.…”

Section: The Neuroprotective Properties Of Pctx1mentioning

confidence: 99%

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

Cristofori-Armstrong

Rash

2017

Neuropharmacology

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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.

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Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Section: The Neuroprotective Properties Of Pctx1mentioning

confidence: 99%

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

Cristofori-Armstrong

Rash

2017

Neuropharmacology

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“…Syn hetic molecules like GMQ po entia e, or even activa e, ASICs. The mos selective modula ors of ASIC channels are coming from animal venoms wi h highly selective cyseine-rich high-affini y polypeptide oxins ha inhibi (Mambalgins, and o a cer ain ex en APETx2) and sometimes activa e (Mi Tx) hese channels [64]. I has been shown human painful inflamma ory exuda es, displaying non-acidic pH; induce a slow constiutive activation of human ASIC3 channels.…”

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confidence: 99%

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

Roy¹

2018

IJCBR

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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...

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“…The known modulators of ASICs can be broadly categorised as metal ions, small molecules, inflammatory mediators and venom peptides 94 . Although there are several small-molecule modulators of ASICs, none of them has the high specificity and potency of ASIC modulators that have been isolated from animal venoms 94 .…”

Section: Modulation Of Asicsmentioning

confidence: 99%

“…Although there are several small-molecule modulators of ASICs, none of them has the high specificity and potency of ASIC modulators that have been isolated from animal venoms 94 .…”

Section: Modulation Of Asicsmentioning

confidence: 99%

Biotechnological applications of spider venom peptides

Er¹

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Spider venoms are a rich source of bioactive compounds with potential biotechnological applications. The overall aim of this project was to isolate and characterise novel spidervenom peptides (SVPs) with potential in two key areas: (1) insect control using orally active insecticidal peptides; (2) improvement of human health with peptide modulators that target acid-sensing ion channels (ASICs).Insect pests are a worldwide problem as they threaten crop yields and spread a multitude of insect-borne diseases. Unfortunately, the armament of commercially available chemical insecticides is rapidly diminishing due to the emergence of insecticide-resistant insect strains as well as deregistrations and use restrictions by regulatory authorities due to environmental and health concerns. This has created an unmet need for new eco-friendly insecticides. Spiders are highly efficient insect predators that utilise venom to rapidly incapacitate prey. As such, many SVPs have potent insecticidal properties. However, as SVPs are injected by the spider, they are generally perceived to lack sufficient oral efficacy to be of practical agrochemical use. Recently, several orally-active insecticidal peptides (OAIP 1-5) were isolated from the venom of the Australian tarantula, Selenotypus plumipes, and shown to be lethal when fed to the termites. Chapter 2 describes the characterisation and structure determination of one of these peptides, OAIP3. The peptide was produced using an efficient E. coli periplasmic expression system that promotes disulfide bond formation in vivo. The insecticidal activity of the recombinant peptide was tested in mealworms, while the structure of the peptide was solved using heteronuclear nuclear magnetic resonance spectroscopy. Structural studies indicated that OAIP3 contains a canonical inhibitor cystine knot motif commonly found in spider venom peptides.In comparison to its native form, recombinant OAIP3 is markedly less potent in mealworms, with ~53% moribund at a dose of 7.6 nmol/g. Sequence and structural homologies with other spider venom peptides indicated that OAIP3 is likely to target insect voltage-gated sodium channels.Spider venoms are a rich source of peptides that target therapeutically-relevant ion channels such as ASICs. Chapter 3 describes the isolation and characterisation of a novel ASIC1a modulator, Hm3a, isolated from spider venom. ASICs are proton-gated ion channels that respond to acidosis. Since their initial discovery more than a decade ago, iii they have been implicated in many neurodegenerative diseases, neuronal damage resulting form ischemia, and pain. Given that spider venoms are a rich source of ion channel modulators, we screened a panel of 30 spider venoms for inhibitory activity on ASIC1a. Through an assay-guided fractionation using reverse-phase high performance liquid chromatography, we isolated a peptide modulator of ASIC1a from the venom of the tarantula Heteroscodra maculata. Recombinant peptide was produced and characterised using two-electrode voltage-clamp elect...

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Pharmacology of acid-sensing ion channels – Physiological and therapeutical perspectives

Cited by 135 publications

References 198 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

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

Biotechnological applications of spider venom peptides

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