Publication Date:
2011-11-19
Description:
Natural products that elicit discomfort or pain represent invaluable tools for probing molecular mechanisms underlying pain sensation. Plant-derived irritants have predominated in this regard, but animal venoms have also evolved to avert predators by targeting neurons and receptors whose activation produces noxious sensations. As such, venoms provide a rich and varied source of small molecule and protein pharmacophores that can be exploited to characterize and manipulate key components of the pain-signalling pathway. With this in mind, here we perform an unbiased in vitro screen to identify snake venoms capable of activating somatosensory neurons. Venom from the Texas coral snake (Micrurus tener tener), whose bite produces intense and unremitting pain, excites a large cohort of sensory neurons. The purified active species (MitTx) consists of a heteromeric complex between Kunitz- and phospholipase-A2-like proteins that together function as a potent, persistent and selective agonist for acid-sensing ion channels (ASICs), showing equal or greater efficacy compared with acidic pH. MitTx is highly selective for the ASIC1 subtype at neutral pH; under more acidic conditions (pH 〈 6.5), MitTx massively potentiates (〉100-fold) proton-evoked activation of ASIC2a channels. These observations raise the possibility that ASIC channels function as coincidence detectors for extracellular protons and other, as yet unidentified, endogenous factors. Purified MitTx elicits robust pain-related behaviour in mice by activation of ASIC1 channels on capsaicin-sensitive nerve fibres. These findings reveal a mechanism whereby snake venoms produce pain, and highlight an unexpected contribution of ASIC1 channels to nociception.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226747/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226747/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bohlen, Christopher J -- Chesler, Alexander T -- Sharif-Naeini, Reza -- Medzihradszky, Katalin F -- Zhou, Sharleen -- King, David -- Sanchez, Elda E -- Burlingame, Alma L -- Basbaum, Allan I -- Julius, David -- F31NS065597/NS/NINDS NIH HHS/ -- P40 RR018300-09/RR/NCRR NIH HHS/ -- P40RR018300-09/RR/NCRR NIH HHS/ -- P41 GM103481/GM/NIGMS NIH HHS/ -- P41RR001614/RR/NCRR NIH HHS/ -- R01NS065071/NS/NINDS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Nov 16;479(7373):410-4. doi: 10.1038/nature10607.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, University of California, San Francisco, California 94158-2517, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22094702" target="_blank"〉PubMed〈/a〉
Keywords:
Acid Sensing Ion Channels
;
Amino Acid Sequence
;
Animals
;
Capsaicin/pharmacology
;
Cells, Cultured
;
Elapid Venoms/*chemistry/*pharmacology
;
*Elapidae
;
Hindlimb/drug effects/physiopathology
;
Humans
;
Hydrogen-Ion Concentration
;
Ion Channel Gating/drug effects
;
Male
;
Mice
;
Mice, Knockout
;
Molecular Sequence Data
;
Nerve Tissue Proteins/agonists/deficiency/genetics/*metabolism
;
Nociception/drug effects/physiology
;
Oocytes
;
Pain/*chemically induced/metabolism/physiopathology
;
*Protein Multimerization
;
Protein Structure, Quaternary
;
Protons
;
Rats
;
Sensory Receptor Cells/drug effects/metabolism
;
Sodium Channel Agonists
;
Sodium Channels/deficiency/genetics/*metabolism
;
TRPV Cation Channels/metabolism
;
Xenopus laevis
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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