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ASICs are also asics nimbus sensitive to amiloride and related compounds; however, the IC 50 values for these drugs are around two to three orders of magnitude greater for ASIC channels as compared with the prototypical renal ENaC channel. In general, much less is known about ASIC regulation than about that for ENaC. Despite this, there are a number of therapeutic opportunities afforded by manipulation of ASIC protein function or expression, including pain states, psychiatric disorders, neurodegenerative diseases, and cancer ( 218 , 412 , 421 , 428 ). The studies detailing the involvement of ASICs in these states come primarily from genetic knockout and inhibitor studies in animal models, though some human data are available.One of the chief indications for a targeted ASIC-based therapy is in the treatment of pain.

The ASIC proteins as well as their characteristic acid-induced currents have been found in many cells of the peripheral nervous system ( 219 , 412 ). It is also known that acidosis accompanies inflammatory and pain states, and recently a peptide toxin isolated from the Texas coral snake, the venom of which causes intense pain, has been found to be an agonist at ASIC1 and ASIC2 channels ( 47 ). These findings suggest that ASICs are involved in nociception as transducers of painful asics kayano 23 stimuli. It had been well established, with initial work from the late 1920s, that protons and acidic solutions caused painful sensations when rapidly applied ( 146 ). Identification of the ASICs and their presence in nociceptive neurons and in dorsal root ganglia rapidly led to their being considered as potential pain transducers ( 7 , 286 , 387 , 399 , 403 ).

ASIC3 expression was also increased in wild-type asics running shoes mice following joint inflammation ( 191 , 192 ). It has been suggested that the presence of channel on afferent nerves following inflammation would be relayed to the spinal cord, which would then integrate increased sensitization into the behavior characteristic of secondary hyperalgesia, and that these findings suggest a role for ASIC3 in the pain associated with arthritis ( 191 , 192 ).Unlike the relatively small changes in [H ] found in the heart, the GI tract and particularly the stomach experiences large excursions in pH during the course of the day. Gastric acid has a pH 372 ). Signaling along the brain-gut axis was also disrupted in ASIC3 knockout mice which had been exposed to iodoacetamide to induce a mild gastritis ( 416 ).

Moreover, recently defined interactions between ASICs and peptides found within the CNS, such as the dynorphins, asics gel nimbus reinforce the possibility that CNS ASICs may be manipulated to manage pain ( 347 , 426 ).In general, and despite data from knockout animals, a reasonable case can be made for ASICs, particularly ASIC3, being attractive targets for novel analgesic strategies. Acid-induced pain in humans was attenuated by treatment with amiloride ( 392 ), suggesting that inhibitors of ASICs, potentially including peptide toxins and aminoglycoside antibiotics ( 145 ), in addition to the more conventional amiloride and NSAID analogs ( 128 ), could play a role in the treatment of pain, while avoiding the behavioral issues associated with opiates ( 272 ). A more detailed account of the literature surrounding the role of ASICs in pain is provided in an excellent recent review ( 98 ).

Studies of ASIC1 in mice have implicated it in synaptic plasticity, learning, and memory formation (409 411). In the CNS, the protein appears to localize with the postsynaptic density-95 protein (PSD-95), which likely targets ASIC1 to areas of high synaptic density ( 409 , 410 ). Behavioral tests of mice overexpressing ASIC1 found increased acquired fear related behavior ( 411 ), while ASIC1 knockout mice showed a deficit in cued and contextual fear conditioning ( 409 ), suggesting that perhaps ASIC1 could play a role in anxiety or fear learning. Interestingly, it has recently been reported that decreased brain pH resulting from hypercarbia also elicits fear in mice, a behavioral response that is attenuated by ASIC1 knockout ( 442 ). However, a case-control twin study showed no association between polymorphisms of ASIC1 and anxiety spectrum disorders ( 175 ).

Still, functional tests with ASIC inhibitors in animal models found that ASIC inhibition was able to produce antidepressive, sedative, and anxiolytic effects ( 88 , 112 , 234 ). For example, amiloride, PcTx1, and A317567 all exhibited anxiolytic activity, with PcTx1 and A317567 being most effective, most likely reflecting the lower potency of amiloride in ASIC inhibition ( 112 ). asics netball shoes The exact role and mechanism of ASIC in anxiety and fear learning remains to be elucidated, but the data suggest that inhibition of ASICs can play a role in the treatment of anxiety or depression states.For example, during ischemic stroke there is a localized reduction in the extracellular pH. This acidosis is hypothesized to activate homomeric ASIC1 channels, leading to elevations of intracellular calcium and cell death. As noted earlier, the P Na /P Ca 2 for homotrimeric rat ASIC1a has been calculated as 2.5 by one group and as Изображение 18.5 by another group ( 33 , 405 ). 18.5 by another group ( 33 , 405 ).

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