ÿþAlthough ASIC3 seems to asics trainers predominate in the mediation of pain signals from the periphery, ASIC1 or composite ASIC1/2 channels may have a more important role in pain sensation in the central nervous system (CNS). ASICs are expressed in the CNS in multiple locations including hippocampus, hypothalamus, midbrain, and cerebellum ( 6 , 215 , 274 , 307 ). While not all of these locations are involved in pain sensing, it is likely that ASICs identified in neurons of the dorsal horn are responsible for integrating peripheral pain signals before transmission to the cortex ( 32 ).

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 asics running shoes 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, asics gel kayano 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 ). 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 asics gt 2000 treatment of anxiety or depression states.

Overexpression of parkin suppressed ASIC2a currents in a heterologous COS-7 cell system, while OAG (1-oleoyl-2-acetyl-sn-glycerol, a PKC activator)-stimulated currents in hippocampal neurons from a parkin knockout mouse were greatly potentiated ( 209 ). In contrast, OAG had no effect on ASIC currents recorded from wild-type mice. These data suggest that hyperactivity of ASIC contributes to neurodegeneration in Parkinson's disease.As with ENaCs, ASICs also have a role in sensory perception. ASICs are expressed in the retina, along with ENaCs ( 56 , 271 ). Retinal ganglion cells, which integrate signals from the retina also express amiloride-sensitive proton activated currents, consistent with ASIC expression ( 246 ).

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 asics netball trainers 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 , 155 , 156 ).