| Acid-sensing ion channels(ASICs) are a class of cation channel which are activated by high concentration of extracellular protons. ASICs are widely expressed in central and peripheral nervous systems. In recent years, ASICs have been reported to be involved in many physiological conditions, such as synaptic transmission and spine development, retinal function, learning and memory, fear conditioning, and plenty of pathological processes, such as nociception, ischemia, seizure, neurodegeneration, etc. As chemical-electrical transducers, ASICs permeate cation(mainly Na+ and Ca2+) influx, thus lead to neuronal depolarization and even neuronal excitability. In this study, we focused on three perspectives of ASIC1 a, the main subunit of ASICs family: the critical domains of intracellular N-terminus that control the channel gating and surface expression; functional regulation by several antiepileptic drugs; its role involved in chronic epileptogenesis.。Previous studies have found that the intracellular carboxyl-terminus(C-terminus) of ASIC1 a has many regulatory sites involved in channel protein expression and gating mechanism, while less information about its intracellular amino-terminus(N-terminus) was reported. Therefore,With various strategies of truncation in ASIC1 a N-terminus, we scanned the cytoplasmic domains of ASIC1 a and found that N-terminus as a whole is involved in ASIC1 a surface expression and there is no specific domain dominating this process. Furthermore, concomitant electrophysiological studies showed that 17-20 amino acids at the internal N-terminus contribute differently to the channel gating of ASIC1 a, while I18 plays a leading role.As a ligand-gated cation channel, ASIC1 a is involved in many physiological and pathological processes, and regulated by many clinical drugs such as non-steroidal anti-inflammatory drugs, anesthetics lidocaine, aminoglycoside antibiotics, suggesting that ASIC1 a is likely to be one of the pharmacologic targets of these drugs. ASIC1 a has been reported involved in epilepsy and neuropathic pain, and most drugs for these two diseases are ion channel regulator. To find out whether thses drugs regulate ASIC1 a, we screened six antiepileptic drugs all of which are modulators on ion channels by electrophysiological technique, and found that lamotrigine inhibites the peak current amplitude of ASIC1 a while topiramate upregulates its function. The regulations of these two drugs are in a subunit selective, concentration-dependent and opening-state dependent manner.There is no unified conclusion on ASIC1a’s role in epilepsy. It was reported that ASIC1 a contributes to the termination of seizure, while some other studies found ASIC1a’s antagonist could prolong the seizure onset. Most previous studies were carried for ASIC1a’s contribution to acute seizures, yet its role in epileptogenesis is still unknown. In the present study, we employed Li-pilocarpine model to mimic chronic epileptogenesis and found that amiloride, a blocker of ASIC1 a, reduces epileptogenic processes and protectes against working memory deficits. Further results that astrocytic but not neuronal ASIC1 a protein is up-expressed in the process of epileptogenesis highlight the important role of astrocytic ASIC1 a.Present study about ASIC1a’s N-terminus provided us some new information to understand the relationship between its structure and functions, and provided an alternative target for the design of drug regulation. Different regulation effects of lamotrigine and topiramate on ASIC1 a may be involed in the two drugs’ different pharmacological effects. More importantly, we found that astrocytic but not neuronal ASIC1 a protein expression increased during chronic epileptogensis and the antagonist of ASIC1 a played a anti-epileptic role. These results provides us with a new clue to explore the mechanism of epilepsy. |
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