Inhibition of Acid Sensing Ion Channel 3 Aggravates Seizures by Regulating NMDAR Function

Abstract

The existing data about whether acid sensing ion channels (ASICs) are proconvulsant or anticonvulsant are controversial. Particularly, acid sensing ion channel 3 (ASIC3) is the most sensitive to extracellular pH and has the characteristic ability to generate a biphasic current, but few studies have focused on the role of ASIC3 in seizure. Here we found ASIC3 expression was increased in the hippocampus of pilocarpine induced seizure rats, as well as in hippocampal neuronal cultures undergoing epileptiform discharge elicited by Mg-free media. Furthermore, ASIC3 blockade by the selective inhibitor APETx2 shortened seizure onset latency and increased seizure severity compared with the control in the pilocarpine induced seizure model. Incubation with APETx2 enhanced the excitability of primary cultured hippocampal neurons in Mg-free media. Notably, the aggravated seizure was associated with upregulation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDARs), increased NMDAR mediated excitatory neurotransmission and subsequent activation of the Ca/calmodulin-dependent protein kinase II (CaMKII) and cAMP-response element binding protein (CREB) signaling pathway. Moreover, co-immunoprecipitation confirmed the interaction between ASIC3 and NMDAR subunits, and NMDARs blockade prevented the aggravated seizure caused by ASIC3 inhibition. Taken together, our findings suggest that ASIC3 inhibition aggravates seizure and potentiates seizure induced hyperexcitability at least partly by the NMDAR/CaMKII/CREB signaling pathway, which implies that ASIC3 agonists may be a promising approach for seizure treatment.

FKN/CX3CR1 axis facilitates migraine-Like behaviour by activating thalamic-cortical network microglia in status epilepticus model rats

“…The induction of status epilepticus using pilocarpine was performed as previously described [ 27 ]. Experimental rats were injected with lithium chloride (127 mg/kg, i.p., Sigma–Aldrich, St. Louis, MO), and 18 to 24 h later, atropine sulfate (1 mg/kg, i.p., Double-Crane pharmaceutical Co., Ltd) was administered to antagonize the peripheral cholinergic effect.…”

Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

“…Meanwhile, TMEM25 can also modulate the degradation of the GluN2B subunit and neuronal excitability (Zhang et al, 2019). Inhibition of acid-sensing ion channel 3 can regulate NMDAR function, thereby aggravating seizure severity (Cao et al, 2018). POSH could be a potential therapeutic target for epilepsy via increasing surface expression of NMDAR (Wang X. et al, 2017).…”

Acid-Sensing Ion Channel 2: Function and Modulation

“…The involvement of ASICs, including ASIC2, is observed in neuronal excitability, especially in relation to imbalances in neuronal excitation seen in seizure and epilepsy [79][80][81]. Amiloride has been shown to reduce generalized seizures induced by either pentylenetetrazole or electrical stimulation [18,82].…”