Acid sensing ion channels are voltage-indipendent, proton activated receptors that belong to the epithelial sodium channel (ENaC)/degenerin family of ion channels and are involved in perception of pain (and also ischaemic stroke, mechanosensation, even in learning and memory).
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
ASICs are trimeric, and each subunit has a short amino and carboxy termini, two transmembrane helices and a multidomain extracellular region enriched in acidic residues and carboxyl-carboxylate pairs. At least one carboxyl group bears a proton, and these carboxyl-carboxylate pairs participate in proton sensing. A disulphide-rich “tumb” domain is between the acidic residues and the transmembrane pore: it may couple the binding of protons to the opening of the ion channel. Structure of acid-sensing ion channel 1 at 1.9 Å resolution and low pH, 2007
Protein Aminoacids Percentage
The Protein Aminoacids Percentage gives useful information on the local environment and the metabolic status of the cell (starvation, lack of essential AA, hypoxia)
Protein Aminoacids Percentage (Width 700 px)
SYNTHESIS AND TURNOVER
ASICs conduct cations, like Na+ and Ca2+, but the physiologically relevant process is ther conductance of Na+. Five subunits (ASIC1a, ASIC1b, ASIC2a, ASIC3b and ASIC3) can combine to form acid-activated channels. The ASIC subunit composition of a channel determines its properties, including pH sensivity: ASIC1a and ASIC3 homomeric channels are activated if the extracellular pH decreases to <7, whereas ASIC2a homomeric channels are activated when pH decreases <6, and the combination of different subunits can produce properties different from those of homomeric channels.
Some molecules that modulated ASIC are arachidonic acid, NO and lactate: they all alter properties as ph sensivity and desensitization.
Tissue injury and inflammation cause acidosis, and acidic pH can trigger pain http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613646/. These observations led to the hypothesis that ASICs, and possibly other acid-activated receptors, have a critical role in nociception, but how ASICs transduce or modulate painful stimuli has not been established yet.
The pH sensitivity of ASICs is the property that most strongly links these channels to pain. Acidification of the skin or muscle produces pain. Even the earliest papers describing H+-activated channels recognized that the channels might function as nociceptors. Inflammation, infection, ischemia and exercise all cause local pH to decrease, frequently to a pH < 7, which is sufficient to activate ASIC1a and ASIC3 channels in vitro. Thus, ASICs are strong candidates for detecting the variations in pH that occur with a variety of painful conditions.
Also ASICs location suggest their involvement in pain: they are expressed in PNS, in CNS and in non-neuronal cells. In PNS, ASIC subunit are expressed in primary afferent fibers. Many of the ASIC-expressing neuron are nociceptive.
Early immunohistochemical studies that identified ASIC1a in substance P-containing neurons of the dorsal root ganglion (DRG) supported the hypothesis that ASICs mediate nociception. Shortly after ASIC1a was identified , ASIC3 was also discovered, and was determined to be localized to primary afferent nociceptive fibers innervating the skin, muscles, joints and viscera. ASIC3 is expressed in a greater number of nociceptive neurons innervating muscle (50%) than skin (10%), suggesting that ASIC3 might be particularly important for detecting muscle acidosis.
- Cell signaling and Ligand transport
- Structural proteins