For example, during ï»¿asics trainers 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 18.5 by another group ( 33 , 405 ). The divergence between these two values is likely due to the difficulties with calculating the permeability for a channel that is allosterically modulated by the divalent cation in question as well as the innate kinetics of the channel, making it difficult to record accurate measurements ( 23 , 38 , 94 , 142 , 195 , 300 ).
This held true for 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 asics running shoes 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 asics gel kayano polyglutamine tract and neuronal damage ( 34 ).
This could not be accounted for by simple neuronal death as treatment with diazepam and pentobarbital, which protect neurons, did not prevent the loss of ASIC message. ASIC1a expression was also reduced, but in a more restricted area. A more recent functional study has demonstrated that ASIC1 activity is, however, important in seizure termination, as seizures in ASIC1 knockout mice were much more severe than in their wild-type counterparts; similar results were obtained when ASIC1 was acutely inhibited in wild-type mice by intracranial injection of PcTx1 ( 443 ). Conversely, overexpression of ASIC1 shortened seizure duration.
Heteromeric ASIC1a/2b channels are asics gt 2000 more sensitive to reductions in pH than either ASIC1a or ASIC2b alone ( 174 ) and reducing extracellular pH (pH o ) to 6.8 was sufficient to decrease seizure activity in hippocampal slices ( 443 ). Loss of ASIC2b would therefore be predicted to decrease sensitivity of a heteromeric channel to changes in pH o . However, it is unknown whether heteromeric or homomeric channels are involved in seizure termination. Furthermore, seizure initiation and termination are highly complex processes, and the involvement of any channel type may differ based on the location of the seizure focus or even between species. Interestingly, expression of ASIC4 has been reported to be induced in pediatric patients with febrile seizures ( 338 ).
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.
ENaC expression asics netball trainers is also upregulated in melanoma cells ( 425 ), while in salivary gland carcinoma cells, an ASIC2/3 heteromeric conductance has been proposed to underlie a proton-gated current that was not present in normal salivary gland epithelia ( 428 ). To date, the best case for involvement of ASICs and ENaCs in tumors has come from studies of colonic and brain malignancies. Using a genetic murine model of colon cancer, the heterozygous APC Min/ mouse, Ousingsawat et al. ( 293 ) found that expression of ±²³ENaC was increased in the distal colon, which corresponded to an increase in sodium absorption.