Pharmacology of <scp>ASIC</scp> channels

Lingueglia, Éric; Lazdunski, Michel

doi:10.1002/wmts.88

Cited by 19 publications

(16 citation statements)

References 186 publications

(322 reference statements)

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“…<Insert Because nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to block ASIC channels with IC50 values in the high micromolar range (90-350 µM) (Lingueglia and Lazdunski, 2013;Voilley, 2004), we examined sensitivity to five NSAID drugs (Fig. 4 A) as an additional window into shared, but variable properties of DEG/ENaC/ASIC channels.…”

Section: Unlike Mec-4d and Unc-8d Degt-1d Is Insensitive To Amiloridmentioning

confidence: 99%

“…The mechanism by which non-steroidal anti-inflammatory drugs or NSAIDs generate analgesia is by inhibiting cyclo-oxygenase-1 (COX-1) and COX-2 enzymes (Day and Graham, 2013;Weissmann, 1991). These compounds also inhibit DEG/ENaC/ASIC channels (Lingueglia and Lazdunski, 2013;Lynagh et al, 2017;Voilley, 2004;Voilley et al, 2001) and P2X channels (Lynagh et al, 2017). We built on these observations and tested C. elegans DEG/ENaC/ASICs for sensitivity to a panel of five NSAIDs (Fig.…”

Section: Sensitivity To Nsaids and Their Analogsmentioning

confidence: 99%

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DEG/ENaC/ASIC channels vary in their sensitivity to anti-hypertensive and non-steroidal anti-inflammatory drugs

Fechner

D'Alessandro

Wang

et al. 2020

Preprint

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The degenerin channels, epithelial sodium channels, and acid-sensing ion channels (DEG/ENaC/ASICs) play important roles in sensing mechanical stimuli, regulating salt homeostasis, or responding to acidification in the nervous system. They share a common topology with two transmembrane domains separated by a large extracellular domain and are believed to assemble as homomeric or heteromeric trimers into non-voltage gated, sodiumselective, and amiloride-sensitive ion channels. Amiloride is not the only drug that targets DEG/ENaC/ASICs, however, they are also emerging as a target of nonsteroidal antiinflammatory drugs (NSAIDs) as well as other classes of small molecules. C. elegans has about 30 genes encoding DEG/ENaC/ASIC subunits and thus offers an excellent opportunity to examine variations in sensitivity to small molecules and biophysical properties. Here, we analyzed a subset of the C. elegans DEG/ENaC/ASIC proteins in order to test the hypothesis that individual family members have distinct properties. Toward this goal, we expressed five C. elegans isoforms in Xenopus laevis oocytes (DEGT-1d, DEL-1d, UNC-8d, MEC-10d and MEC-4d) and measured current amplitude, selectivity among monovalent cations, sensitivity to amiloride and its analogs, and sensitivity to NSAIDs. Of these five proteins, only DEGT-1d, UNC-8d, and MEC-4d form homomeric channels. Unlike MEC-4d and UNC-8d, DEGT-1d channels were insensitive to amiloride and its analogs and more permeable to K + than to Na + . As reported for rat ASIC1a, NSAIDs inhibit DEGT-1d and UNC-8d. Unexpectedly, MEC-4d was strongly potentiated by NSAIDs, an effect that was decreased by mutations in the extracellular domain that affect inhibition of rat ASIC1a. Collectively, these findings reveal that not all DEG/ENaC/ASIC channels are amiloride-sensitive and sodium-selective and that NSAIDs can both inhibit and potentiate these channels.The degenerin channels, epithelial sodium channels, and acid-sensing ion channels (DEG/ENaC/ASICs) are present in most, if not all metazoans and expressed in diverse tissues, including the epithelia of several organs and in the central and peripheral nervous systems (Eastwood and Goodman, 2012; Kellenberger and Schild, 2002). These channels vary in how they are activated in vivo, although the activation mechanisms are not yet known for all family members. At least two DEG proteins are known to be mechanosensitive, ENaCs are constitutively active and can be regulated by shear stress, and ASICs are activated by proton binding (Eastwood and Goodman, 2012). The DEG and ENaC proteins were the initial members of this superfamily. The DEGs were identified in C. elegans by virtue of their role in mechanosensation and neuronal degeneration (Chalfie and Wolinsky, 1990; Driscoll and Chalfie, 1991; Huang and Chalfie, 1994). The ENaCs were identified via expression of rodent cRNAs in Xenopus oocytes followed by functional screening (Canessa et al., 1995). The proteins that form acid-sensing ion channels (ASICs) were also identified in the 1990s (Waldman...

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Section: Unlike Mec-4d and Unc-8d Degt-1d Is Insensitive To Amiloridmentioning

confidence: 99%

Section: Sensitivity To Nsaids and Their Analogsmentioning

confidence: 99%

DEG/ENaC/ASIC channels vary in their sensitivity to anti-hypertensive and non-steroidal anti-inflammatory drugs

Fechner

D'Alessandro

Wang

et al. 2020

Preprint

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“…ASICs are cation-selective, proton-gated ion channels associated with nociception and other physiological processes and they are a promising target for the treatment of inflammatory pain as well as a range of neurological disorders. [26][27][28][29][30] PcTx1 is a 40-residue peptide with a inhibitory cysteine knot motif isolated from the venom of the tarantula Psalmopoeus cambridgei. It is the most potent and selective blocker of ASIC1 known.…”

Section: Introductionmentioning

confidence: 99%

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Deplazes

Davies

Bonvin

et al. 2015

J. Chem. Inf. Model.

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Peptides that bind to ion channels have attracted much interest as potential lead molecules for the development of new drugs and insecticides. However, the structure determination of large peptidechannel complexes using experimental methods is challenging. Thus structural models are often derived from combining experimental information with restraint-driven docking approaches. Using the complex formed by the venom peptide PcTx1 and the acid sensing ion channel (ASIC) 1a as a case study, we have examined the effect of different combinations of restraints and input structures on the statistical likelihood of (a) correctly predicting the structure of the binding interface and (b) the ability to predict which residues are involved in specific pairwise peptide-channel interactions. For this, we have analyzed over 200 000 water-refined docked structures obtained with various amounts and types of restraints of the peptidechannel complex predicted using the docking program HADDOCK. We found that increasing the number of restraints or even the use of pairwise interaction data resulted in only a modest improvement in the likelihood of finding a structure within a given accuracy. This suggests that shape complementarity and the force field make a large contribution to the accuracy of the predicted structure. The results also showed that there are large variations in the accuracy of the predicted structure depending on the precise combination of residues used as restraints. Finally, we reflect on the limitations of relying on geometric criteria such as root-mean square deviations to assess the accuracy of docking procedures. We propose that in addition to currently used measures, the likelihood of finding a structure within a given level of accuracy should be also used to evaluate docking methods.

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“…Acid-sensing ion channel 3 (ASIC3) is the most sensitive acid sensor (pH 0.5 activation ~6.7) predominantly expressed in the peripheral sensory neurons [ 1 , 2 ]. It can be activated by low extracellular pH to evoke both transient and sustained inward currents, which can be further enhanced by lactate [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Abnormal Cardiac Autonomic Regulation in Mice Lacking ASIC3

Cheng

Kuo²,

Chen

et al. 2014

BioMed Research International

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Integration of sympathetic and parasympathetic outflow is essential in maintaining normal cardiac autonomic function. Recent studies demonstrate that acid-sensing ion channel 3 (ASIC3) is a sensitive acid sensor for cardiac ischemia and prolonged mild acidification can open ASIC3 and evoke a sustained inward current that fires action potentials in cardiac sensory neurons. However, the physiological role of ASIC3 in cardiac autonomic regulation is not known. In this study, we elucidate the role of ASIC3 in cardiac autonomic function using Asic3 −/− mice. Asic3 −/− mice showed normal baseline heart rate and lower blood pressure as compared with their wild-type littermates. Heart rate variability analyses revealed imbalanced autonomic regulation, with decreased sympathetic function. Furthermore, Asic3 −/− mice demonstrated a blunted response to isoproterenol-induced cardiac tachycardia and prolonged duration to recover to baseline heart rate. Moreover, quantitative RT-PCR analysis of gene expression in sensory ganglia and heart revealed that no gene compensation for muscarinic acetylcholines receptors and beta-adrenalin receptors were found in Asic3 −/− mice. In summary, we unraveled an important role of ASIC3 in regulating cardiac autonomic function, whereby loss of ASIC3 alters the normal physiological response to ischemic stimuli, which reveals new implications for therapy in autonomic nervous system-related cardiovascular diseases.

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Pharmacology of ASIC channels

Cited by 19 publications

References 186 publications

DEG/ENaC/ASIC channels vary in their sensitivity to anti-hypertensive and non-steroidal anti-inflammatory drugs

DEG/ENaC/ASIC channels vary in their sensitivity to anti-hypertensive and non-steroidal anti-inflammatory drugs

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Abnormal Cardiac Autonomic Regulation in Mice Lacking ASIC3

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