The Roles Of Acid-sensing Ion Channel 1a(ASIC1a) In Acidosis-induced Neuronal Injuries

In recent years,acid-induced signaling has attracted more and more attention in neuroscience research.Synaptic transmission reduces pH at the synaptic cleft,and this acidification contributes to postsynaptic currents and synaptic plasticity.Moreover,acidosis is common in neurologic diseases and is a major cause of neuronal injuries in diseases,such as ischemia.These observations indicate that proton-mediated signaling is important for both physiologic and pathophysiological responses.Acid-sensing ion channels(ASICs)are the major proton receptor in the brain,a family of proton-gated cation channels.ASICs conduct mostly Na+,also have a low permeability to Ca2+.ASICs have six subunits:ASICla,ASIClb,ASIC2a,ASIC2b,ASIC3,ASIC4.ASIC 1a is a key mediator of acidosis-induced neuronal injuries in diseases.ASIC 1a-/-mice exhibit deficits in hippocampal long term potentiation and learning.ASIC 1a-/-mice show changes in fear-and anxiety-related behavior.Most of published data on ASIC function came from studies performed in mice,and relatively little is known about potential differences between human and mouse ASICs.This information is critical for us to better interpret the functional importance of ASICs in human diseases.In our study,we treated the cultured hippocampus brain slices with acidosis,neuronal injuries is increased in pH6.0 acidic solution.At pH6.0,Ca2+ level of intracellular is increased,which increased the phosphorylation of CaMKII and PKCss in the hippocampus slices.ASIC 1a mediated acidosis-induced Ca2+increase in the neuron.ASIC la also mediated the acidosis-induced neuronal injuries.Here,we examined the expression of ASICs in acutely resected human cortical tissue.Compared to mouse cortex,human cortical tissue showed a similar ratio of ASIC la;ASIC2a expression,had reduced ASIC2b level,and exhibited a higher membrane:total ratio of ASICla.Human ASICla exhibits higher surface trafficking than mouse ASIC la in heterologous cells.Human ASIC la also exhibits larger acid-induced current in whole cell patch clamp.We further investigated the mechanism for higher surface trafficking of human ASIC1a.Although mouse ASICla and human ASICla share high homology(99%amino acid identity),A single amino acid at position 285 was critical for increased surface expression of human ASICla.Consistent with the changes in trafficking and current,cells expressing human ASICla or mouse ASICla S285P mutant had higher acid-activated calcium increase,and exhibited worsened acidotoxicity.These data suggest that ASICs are likely to have a larger impact on acidosis-induced neuronal injuries in human than mice,and this effect is,at least in part,due to more efficient trafficking of human ASICla.