α-Dendrotoxin inhibits the ASIC current in dorsal root ganglion neurons from rat

Báez, Adriana; Salceda, Emilio; Fló, Martín; Graña, Martín; Fernández, Cecilia; Vega, Rosario; Soto, Enrique

doi:10.1016/j.neulet.2015.08.034

Cited by 21 publications

(12 citation statements)

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“…Taking into account the recently described activity of α-DTX on ASIC currents in DRG neurons [ 22 ], we also analyzed the effect of Eg KU-1 and Eg KU-4 on pH-dependent Na + currents. The sustained application of both Eg KUs blocked the ASIC currents elicited by a pH change from 7.4 to 6.1.…”

Section: Resultsmentioning

confidence: 99%

“…We recently reported that α-DTX, the well-known blocker of voltage activated K + channels, also inhibits ASIC currents in rat DRG, although with significantly less potency than K v (IC 50 ~ 10 −7 M [ 22 ] versus 10 −9 M [ 29 ], respectively; see also Figs 4 and 8B ). This result indicates that the Kunitz domain is yet another structural scaffold for ASIC-blocking polypeptides.…”

Section: Discussionmentioning

confidence: 98%

“…This result indicates that the Kunitz domain is yet another structural scaffold for ASIC-blocking polypeptides. Interestingly, an exposed basic-aromatic cluster identified in structurally different ASIC blocking peptides [ 33 ] was also found to be present in the structure of α-DTX [ 22 ]. Notably, this feature is observable towards one side of the model structures of Eg KU-1 and Eg KU-4 and not in those of Eg KU-3/ Eg KU-8 ( Fig 10A ).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, patch-clamp assays on rat dorsal root ganglion (DRG) neurons confirmed that Eg KU-1, and also its close paralog Eg KU-4, block K v . Furthermore, the two proteins also block pH-dependent sodium channels (acid sensing ion channels, ASICs), a previously unreported activity for Kunitz inhibitors, that we recently described for α-DTX [ 22 ]. In addition, we provide further evidence of the presence of Eg KUs in parasite secretions.…”

Section: Introductionmentioning

confidence: 99%

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Functional diversity of secreted cestode Kunitz proteins: Inhibition of serine peptidases and blockade of cation channels

et al. 2017

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We previously reported a multigene family of monodomain Kunitz proteins from Echinococcus granulosus (EgKU-1-EgKU-8), and provided evidence that some EgKUs are secreted by larval worms to the host interface. In addition, functional studies and homology modeling suggested that, similar to monodomain Kunitz families present in animal venoms, the E. granulosus family could include peptidase inhibitors as well as channel blockers. Using enzyme kinetics and whole-cell patch-clamp, we now demonstrate that the EgKUs are indeed functionally diverse. In fact, most of them behaved as high affinity inhibitors of either chymotrypsin (EgKU-2-EgKU-3) or trypsin (EgKU-5-EgKU-8). In contrast, the close paralogs EgKU-1 and EgKU-4 blocked voltage-dependent potassium channels (Kv); and also pH-dependent sodium channels (ASICs), while showing null (EgKU-1) or marginal (EgKU-4) peptidase inhibitory activity. We also confirmed the presence of EgKUs in secretions from other parasite stages, notably from adult worms and metacestodes. Interestingly, data from genome projects reveal that at least eight additional monodomain Kunitz proteins are encoded in the genome; that particular EgKUs are up-regulated in various stages; and that analogous Kunitz families exist in other medically important cestodes, but not in trematodes. Members of this expanded family of secreted cestode proteins thus have the potential to block, through high affinity interactions, the function of host counterparts (either peptidases or cation channels) and contribute to the establishment and persistence of infection. From a more general perspective, our results confirm that multigene families of Kunitz inhibitors from parasite secretions and animal venoms display a similar functional diversity and thus, that host-parasite co-evolution may also drive the emergence of a new function associated with the Kunitz scaffold.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional diversity of secreted cestode Kunitz proteins: Inhibition of serine peptidases and blockade of cation channels

et al. 2017

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“…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]. Recen ly discovered ASIC inhibi or compound 5b, one of he mos po en inhibi ors known o da e, lacks sub ype selectivi y [62].…”

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

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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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Evolutionary Aspects of the Structural Convergence and Functional Diversification of Kunitz-Domain Inhibitors

Mishra

2020

J Mol Evol

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α-Dendrotoxin inhibits the ASIC current in dorsal root ganglion neurons from rat

Cited by 21 publications

References 33 publications

Functional diversity of secreted cestode Kunitz proteins: Inhibition of serine peptidases and blockade of cation channels

Functional diversity of secreted cestode Kunitz proteins: Inhibition of serine peptidases and blockade of cation channels

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

Evolutionary Aspects of the Structural Convergence and Functional Diversification of Kunitz-Domain Inhibitors

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