Gating Mechanism and Movements in Acid Sensing Ion Channel 1A

Abstract

Acid Sensing Ion Channels (ASICs) are proton sensitive ion channels found in central and peripheral nervous system. They are involved in a variety of physiological processes including sensory perception, synaptic transmission and nociception. It is also involved in pathological processes like stroke and hypoxia leading to cell death. Thus understanding the mechanism of working of these ion channels are of importance in order to be able to design modulators. Here we present results from a combination of biophysical, molecular, functional and computational studies that looks at various aspects of ASIC functions. Earlier studies pointed towards possible involvement of carboxylate residues in the extracellular domain, in pH sensing. Our results indicate that there are three carboxylate pairs that are involved in gating. The carboxylates upon proton binding, induce a conformational change that causes the finger and thumb domains of ASIC come closer to each other. Our results indicate that these carboxylate pairs and the conformational change are key factors that mediate gating of the ion channel. We then proceeded to study the inter subunit conformational changes that might be involved in desensitization process. Biophysical investigations indicate that the subunits move away from each other upon desensitization. This movement is not global between the subunits. The segments closer to the central vestibule stay relatively in the same position whereas the residues towards the periphery of the ion channel moves away from each other more prominently. These results show that the ion channel undergoes a lateral flowering-like motion during desensitization in comparison with the resting state of the ion channel.