The modulation of acid-sensing ion channel 1 by PcTx1 is pH-, subtype- and species-dependent: Importance of interactions at the channel subunit interface and potential for engineering selective analogues

Cristofori-Armstrong, Ben; Saez, Natalie J.; Chassagnon, Irène R.; King, Glenn F.; Rash, Lachlan D.

doi:10.1016/j.bcp.2019.03.004

Cited by 28 publications

(50 citation statements)

References 32 publications

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“…Indeed, amiloride demonstrates low selectivity on ASICs, inhibiting ASIC1a, ASIC1b, ASIC2a, and activating homomeric ASIC3 and heteromeric ASIC3/ASIC1b-channels at a neutral pH [ 40 , 41 ]. PcTx1 inhibits ASIC1a [ 42 ], ASIC1a/2b [ 43 ], and ASIC1a/2a [ 44 ], and activates the ASIC1b isoform [ 45 ] and ASIC1a/ASIC2a heteromeric channels [ 46 ]. In contrast, in the central nervous system, mambalgin-2 selectively inhibits only homo and heteroreceptors containing ASIC1a [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a

Bychkov

Shulepko

Osmakov

et al. 2020

Cancers

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Gliomas are fast growing and highly invasive brain tumors, characterized by tumor microenvironment acidification that drives glioma cell growth and migration. Channels containing Acid-sensing Ion Channel 1a subunit (ASIC1a) mediate amiloride-sensitive cation influx in late stage glioma cells, but not in normal astrocytes. Thus, selective targeting of ASIC1a can be a perspective strategy for glioma treatment. Here, ASIC1a expression in U251 MG and A172 glioma cells, but not in normal astrocytes, was demonstrated. Recombinant analog of mambalgin-2 from black mamba Dendroaspis polylepis inhibited amiloride-sensitive currents at ASIC1a both in Xenopus laevis oocytes and in U251 MG cells, while its mutants with impaired activity towards this channel did not. Mambalgin-2 inhibited U251 MG and A172 glioma cells growth with EC50 in the nanomolar range without affecting the proliferation of normal astrocytes. Notably, mambalgin-2 mutants did not affect glioma cell proliferation, pointing on ASIC1a as the main molecular target of mambalgin-2 in U251 MG and A172 cells. Mambalgin-2 induced a cell cycle arrest, inhibited Cyclin D1 and cyclin-dependent kinases (CDK) phosphorylation and caused apoptosis in U251 MG and A172 cells. Moreover, mambalgin-2 inhibited the growth of low-passage primary cells from a patient with glioblastoma. Altogether, our data point to mambalgin-2 as a useful hit for the development of new drugs for glioma treatment.

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Section: Discussionmentioning

confidence: 99%

Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a

Bychkov

Shulepko

Osmakov

et al. 2020

Cancers

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“…For example, altered pH or mutations within the toxin (Arg27Ala or Phe30Ala) can effectively convert PcTx1 into a potentiator) (31,55). Similarly, and depending on cellular context and presence of co-factors, DynA can act as both an inhibitor and potentiator of glutamate receptors (4).…”

Section: Possible Biological Implicationsmentioning

confidence: 99%

Mechanism and site of action of big dynorphin on ASIC1a

Borg

Braun

Heusser

et al. 2019

Preprint

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Acid-sensing ion channels (ASICs) are proton-gated cation channels that contribute to synaptic plasticity, as well as initiation of pain and neuronal death following ischemic stroke.As such, there is a great interest in understanding the in vivo regulation of ASICs, especially by endogenous neuropeptides that potently modulate ASICs. The most potent endogenous ASIC modulator known to date is the opioid neuropeptide big dynorphin (BigDyn). BigDyn is upregulated in chronic pain and increases ASIC-mediated neuronal death during acidosis. Understanding the mechanism and site of action of BigDyn on ASICs could thus enable the rational design of compounds potentially useful in the treatment of pain and ischemic stroke. To this end, we employ a combination of electrophysiology, voltage-clamp fluorometry, synthetic BigDyn analogs and non-canonical amino acidmediated photocrosslinking. We demonstrate that BigDyn binding induces ASIC1a conformational changes that are different from those induced by protonation and likely represent a distinct closed state. Using alanine-substituted BigDyn analogs, we find that the BigDyn modulation of ASIC1a is mediated through electrostatic interactions of basic amino acids in the BigDyn N-terminus. Furthermore, neutralizing acidic amino acids in the ASIC1a extracellular domain reduces BigDyn effects, suggesting a binding site at the acidic pocket. This is confirmed by photocrosslinking using the non-canonical amino acid azidophenylalanine. Overall, our data define the mechanism of how BigDyn modulates ASIC1a, identify the acidic pocket as the binding site for BigDyn and thus highlight this cavity as an important site for the development of ASIC-targeting therapeutics.Note: This manuscript has not been peer-reviewed 3

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“…The first potent and moderately selective ASIC1a ligand discovered is PcTx1, a 40-residue peptide from venom of the Trinidad chevron tarantula Psalmopoeus cambridgei [144]. PcTx1 inhibits homomeric ASIC1a (IC 50~1 nM), ASIC1a/2b heteromers (IC 50~3 nM), and ASIC1a/2a (35-85% inhibition at 50 nM) channels, and potentiates proton-evoked ASIC1b currents by over 3-fold control (EC 50~2 5 nM) [144][145][146][147][148].…”

Section: Spider Toxins Highlight the Role Of Asic1a In Stroke-inducedmentioning

confidence: 99%

Animal toxins — Nature’s evolutionary-refined toolkit for basic research and drug discovery

Herzig

Cristofori-Armstrong

Israel

et al. 2020

Biochemical Pharmacology

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105

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Venomous animals have evolved toxins that interfere with specific components of their victim's core physiological systems, thereby causing biological dysfunction that aids in prey capture, defense against predators, or other roles such as intraspecific competition. Many animal lineages evolved venom systems independently, highlighting the success of this strategy. Over the course of evolution, toxins with exceptional specificity and high potency for their intended molecular targets have prevailed, making venoms an invaluable and almost inexhaustible source of bioactive molecules, some of which have found use as pharmacological tools, human therapeutics, and bioinsecticides. Current biomedically-focused research on venoms is directed towards their use in delineating the physiological role of toxin molecular targets such as ion channels and receptors, studying or treating human diseases, targeting vectors of human diseases, and treating microbial and parasitic infections. We provide examples of each of these areas of venom research, highlighting the potential that venom molecules hold for basic research and drug development.

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The modulation of acid-sensing ion channel 1 by PcTx1 is pH-, subtype- and species-dependent: Importance of interactions at the channel subunit interface and potential for engineering selective analogues

Cited by 28 publications

References 32 publications

Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a

Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a

Mechanism and site of action of big dynorphin on ASIC1a

Animal toxins — Nature’s evolutionary-refined toolkit for basic research and drug discovery

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