This held true for converse white leather COS-7 cells exogenously expressing rat ASIC1a as well as for hippocampal neurons natively expressing rat ASICs ( 429 ). However, heteromeric channels formed of ASIC1 and ASIC2 are calcium impermeable. In rat models, global ischemia upregulated ASIC2 expression which would theoretically increase the population of heteromeric ASIC1/ASIC2 channels, acting to protect neurons from further ischemic attacks ( 210 ).Another mechanism of action was postulated for the role of ASICs in Huntington's disease, where mutations in the huntingtin gene lead to the accumulation of a mutant protein with an expanded polyglutamine tract and neuronal damage ( 34 ).

Still, this work is promising and suggests a role for ASICs in this disease and possibly other CNS diseases where protein aggregation leads to neuronal death.Increased activity of ASICs has been comme des garcons converse implicated in both epilepsy and Parkinson's disease. Chemically induced seizures in rats are associated with a decrease in extracellular pH ( 351 ), likely due to efflux of lactic acid into the extracellular space. This raised the possibility that ASICs could be involved during converse all stars seizure activity. Using pilocarpine to induce status epilepticus, Biagini et al. ( 45 ) found that the message level for ASIC2b was quickly (within 15 min), significantly, and persistently (sustained for at least 24 h) decreased in the hippocampus.

These results suggest the involvement of ASIC1 in neuronal loss, but the relative nonspecificity of the agents used suggests that these data should be interpreted with caution. However, a role for ASIC2a in Parkinson's disease has emerged from studies of parkin , an E3 ubiquitin ligase that is mutated off white converse in genetically related autosomal recessive Parkinson's disease. One target of parkin appears to be PICK1 (protein interacting with C kinase 1), a protein that binds to the COOH-terminal PDZ motif of ASIC1 and ASIC2 ( 110 , 182 ), and which potentiates ASIC-related currents ( 31 , 184 ).

Retinal neurons do experience pH fluctuations, and ASICs in this location may serve to modulate excitability. ASIC1a is found throughout the retina, including cones; inhibition with PcTx1 or knockout of ASIC1 using antisense oligonucleotides resulted in attenuation of the normal response to light as evidenced in the electroretinogram ( 121 ). In contrast, studies in ASIC2 knockout mice showed that this ASIC subunit sensitized the retina to light, and suggested that it had a negative effect on phototransduction ( 123 ). Consistent with this was the finding that ASIC2 knockout mice were more susceptible to light-induced retinal degeneration than their wild-type counterparts.

Touch sensation also involves ASICs, although the exact role of the different channels converse cdg is still somewhat unclear. Pacinian corpuscles express ASIC1 and 2 in humans ( 62 ), although loss of ASIC1 expression did not appear to affect touch sensation in mice ( 294 ). In contrast, ASIC3 has been suggested to be the important mediator of touch sensation in mice ( 315 ).One of the major pathologies for which a potential role of ASICs and ENaCs is currently emerging is cancer. Multiple studies have shown that ASICs and ENaCs are associated with cell migration and proliferation, even in nontumor cells ( 48 , 83 , 97 , , 83 , 97 , 155 , 156 ).