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Individual differences |
Methods | Statistics | Clinical | Educational | Industrial | Professional items | World psychology |
Biological: Behavioural genetics · Evolutionary psychology · Neuroanatomy · Neurochemistry · Neuroendocrinology · Neuroscience · Psychoneuroimmunology · Physiological Psychology · Psychopharmacology (Index, Outline)
Acid-Sensing Ion Channels (ASICs) are neuronal voltage-insensitive cationic channels activated by extracellular protons. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. To date five proteins of the ASIC family have been identified that arise from four genes, ASIC1, ASIC2, ASIC3, and ASIC4. ASIC1a, 1b and 2a, 2b are splice variants. ASICs are trimeric and can be made up of different combinations of subunits. ASIC2b is non functional on its own but modulates channel activity when participating in heteromultimers. ASIC4 has no known function. All ASICs are expressed in the peripheral nervous system while ASIC1a, 2a, 2b and 4 are expressed in the central nervous system. ASICs are Na+ permeable with ASIC1a showing low Ca++ permeability.
The crystal structure of chicken ASIC1a was solved in 2007.
ASICs are potential drug targets for treating a wide variety of conditions linked to both the CNS and PNS. Of particular interest to pain field is the ASIC3 subtype receptor, which is specifically expressed in nociceptors. This subtype exhibits a biphasic current upon proton activation, where the initial inward Na+ current is shortly followed by a sustained cationic current.
ASICs are activated by protons (H+). The concentration of H+ required to open the channel varies with the channels subunit composition (pH from 7 to 5). A snake toxin (MitTx) was recently shown to directly activate ASIC channels and cause pain in mice.
The diuretic amiloride blocks ASICs by acting as pore blocker.
Two animal toxins have been shown to inhibit ASICs channel function. Psalmotoxin-1 (PcTx1) specifically inhibits ASIC1a homomultimeric channels with sub-nanomolar affinity. The sea anemone toxin APETx2 inhibits ASIC3-containing channels with IC50<100 nM.
Results first reported in Nature in October 2012 suggest that a newly discovered class of three-finger peptides from the venom of the black mamba, named mambalgins by the researchers, suppress pain in mice without toxicity and with fewer side effects than morphine. The analgesic effects are believed to involve "blockade of heteromeric channels made of ASIC1a and ASIC2a subunits in central neurons and of ASIC1b-containing channels in nociceptors".
- ↑ Jasti J, Furukawa H, Gonzales EB, Gouaux E (September 2007). Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.. Nature 449 (7160): 316–323.
- ↑ Sluka KA, Winter OC, Wemmie JA (September 2009). Acid-sensing ion channels: A new target for pain and CNS diseases. Curr Opin Drug Discov Devel 12 (5): 693–704.
- ↑ DOI:10.1038/nature11494
- ↑ Gallagher, James Black mamba venom is 'better painkiller' than morphine. BBC News Health. BBC. URL accessed on 3 October 2012.
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