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Nature
2012 Oct 25;4907421:552-5. doi: 10.1038/nature11494.
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Black mamba venom peptides target acid-sensing ion channels to abolish pain.
Diochot S
,
Baron A
,
Salinas M
,
Douguet D
,
Scarzello S
,
Dabert-Gay AS
,
Debayle D
,
Friend V
,
Alloui A
,
Lazdunski M
,
Lingueglia E
.
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Polypeptide toxins have played a central part in understanding physiological and physiopathological functions of ion channels. In the field of pain, they led to important advances in basic research and even to clinical applications. Acid-sensing ion channels (ASICs) are generally considered principal players in the pain pathway, including in humans. A snake toxin activating peripheral ASICs in nociceptive neurons has been recently shown to evoke pain. Here we show that a new class of three-finger peptides from another snake, the black mamba, is able to abolish pain through inhibition of ASICs expressed either in central or peripheral neurons. These peptides, which we call mambalgins, are not toxic in mice but show a potent analgesic effect upon central and peripheral injection that can be as strong as morphine. This effect is, however, resistant to naloxone, and mambalgins cause much less tolerance than morphine and no respiratory distress. Pharmacological inhibition by mambalgins combined with the use of knockdown and knockout animals indicates that blockade of heteromeric channels made of ASIC1a and ASIC2a subunits in central neurons and of ASIC1b-containing channels in nociceptors is involved in the analgesic effect of mambalgins. These findings identify new potential therapeutic targets for pain and introduce natural peptides that block them to produce a potent analgesia.
Altschul,
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
1997, Pubmed
Altschul,
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
1997,
Pubmed
Askwith,
Acid-sensing ion channel 2 (ASIC2) modulates ASIC1 H+-activated currents in hippocampal neurons.
2004,
Pubmed
Baker,
Electrostatics of nanosystems: application to microtubules and the ribosome.
2001,
Pubmed
Baron,
Acid sensing ion channels in dorsal spinal cord neurons.
2008,
Pubmed
Baron,
ASIC-like, proton-activated currents in rat hippocampal neurons.
2002,
Pubmed
Basbaum,
Cellular and molecular mechanisms of pain.
2009,
Pubmed
Bladen,
Taking a bite out of pain: snake venom can be both a curse and a cure when targeting acid sensing ion channels (ASICs) in the pain pathway.
2013,
Pubmed
Bohlen,
A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain.
2011,
Pubmed
,
Xenbase
Bässler,
Molecular and functional characterization of acid-sensing ion channel (ASIC) 1b.
2001,
Pubmed
,
Xenbase
Chen,
MolProbity: all-atom structure validation for macromolecular crystallography.
2010,
Pubmed
Chen,
Unmasking venom gland transcriptomes in reptile venoms.
2002,
Pubmed
Chen,
A sensory neuron-specific, proton-gated ion channel.
1998,
Pubmed
Deval,
Acid-sensing ion channels (ASICs): pharmacology and implication in pain.
2010,
Pubmed
Deval,
ASIC3, a sensor of acidic and primary inflammatory pain.
2008,
Pubmed
Deval,
Acid-sensing ion channels in postoperative pain.
2011,
Pubmed
Diochot,
A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons.
2004,
Pubmed
,
Xenbase
Douguet,
Easier threading through web-based comparisons and cross-validations.
2001,
Pubmed
Edgar,
MUSCLE: multiple sequence alignment with high accuracy and high throughput.
2004,
Pubmed
Escoubas,
Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels.
2000,
Pubmed
,
Xenbase
Fitzjohn,
An electrophysiological characterisation of long-term potentiation in cultured dissociated hippocampal neurones.
2001,
Pubmed
Flemming,
Analgesics: Deadly snake venom for pain relief?
2012,
Pubmed
Fromy,
Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers.
2012,
Pubmed
Jasti,
Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.
2007,
Pubmed
Jones,
Acid-induced pain and its modulation in humans.
2004,
Pubmed
Kini,
Structure, function and evolution of three-finger toxins: mini proteins with multiple targets.
2010,
Pubmed
König,
Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin.
1996,
Pubmed
Labesse,
Incremental threading optimization (TITO) to help alignment and modelling of remote homologues.
1998,
Pubmed
Lewis,
Therapeutic potential of venom peptides.
2003,
Pubmed
Lingueglia,
A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells.
1997,
Pubmed
Malmberg,
Effect of continuous intrathecal infusion of omega-conopeptides, N-type calcium-channel blockers, on behavior and antinociception in the formalin and hot-plate tests in rats.
1995,
Pubmed
Mamet,
Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels.
2002,
Pubmed
Mazzuca,
A tarantula peptide against pain via ASIC1a channels and opioid mechanisms.
2007,
Pubmed
Nakashima,
Accelerated evolution in the protein-coding regions is universal in crotalinae snake venom gland phospholipase A2 isozyme genes.
1995,
Pubmed
Schmidtko,
Ziconotide for treatment of severe chronic pain.
2010,
Pubmed
Schweitz,
Purification and pharmacological characterization of peptide toxins from the black mamba (Dendroaspis polylepis) venom.
1990,
Pubmed
Sherwood,
Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death.
2011,
Pubmed
,
Xenbase
Shi,
FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure-dependent gap penalties.
2001,
Pubmed
Söding,
Protein homology detection by HMM-HMM comparison.
2005,
Pubmed
Terlau,
Conus venoms: a rich source of novel ion channel-targeted peptides.
2004,
Pubmed
Tsetlin,
Snake venom alpha-neurotoxins and other 'three-finger' proteins.
1999,
Pubmed
Vanegas,
Effects of antagonists to high-threshold calcium channels upon spinal mechanisms of pain, hyperalgesia and allodynia.
2000,
Pubmed
Waldmann,
A proton-gated cation channel involved in acid-sensing.
1997,
Pubmed
,
Xenbase
Wemmie,
The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory.
2002,
Pubmed
Woolf,
Overcoming obstacles to developing new analgesics.
2010,
Pubmed
Zhou,
SPARKS 2 and SP3 servers in CASP6.
2005,
Pubmed