Coupling between NMDA Receptor and Acid-Sensing Ion Channel Contributes to Ischemic Neuronal Death

Abstract

Acid-sensing ion channels (ASICs) composed of ASIC1a subunit exhibit a high Ca(2+) permeability and play important roles in synaptic plasticity and acid-induced cell death. Here, we show that ischemia enhances ASIC currents through the phosphorylation at Ser478 and Ser479 of ASIC1a, leading to exacerbated ischemic cell death. The phosphorylation is catalyzed by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity, as a result of activation of NR2B-containing N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) during ischemia. Furthermore, NR2B-specific antagonist, CaMKII inhibitor, or overexpression of mutated form of ASIC1a with Ser478 or Ser479 replaced by alanine (ASIC1a-S478A, ASIC1a-S479A) in cultured hippocampal neurons prevented ischemia-induced enhancement of ASIC currents, cytoplasmic Ca(2+) elevation, as well as neuronal death. Thus, NMDAR-CaMKII cascade is functionally coupled to ASICs and contributes to acidotoxicity during ischemia. Specific blockade of NMDAR/CaMKII-ASIC coupling may reduce neuronal death after ischemia and other pathological conditions involving excessive glutamate release and acidosis.

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

“…The widespread expression of ASIC1a in the brain, its activation by pH drop to the level commonly seen in ischemic brain, and its demonstrated permeability to Ca 2+ strongly suggested that activation of ASIC1a might be involved in the pathology of brain injury. Indeed, a series of recent studies have clearly demonstrated a role for ASIC1a activation in acidosis-mediated and ischemic brain injury [10,12,38,39]. In cultured mouse cortical neurons, activation of ASICs by brief acid incubation induces glutamate receptor-independent Ca 2+ -dependent neuronal injury that is inhibited by specific and non-specific ASIC1a blockade, and by ASIC1 gene knockout [10].…”

Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death

“…It is generally accepted that ASIC1a forms plasma membrane channels that mediate acidosis-induced neuronal death. 5,6 To determine the specificity of ASIC1a in mediating neuronal death induced by different causes, we compared effects of H 2 O 2 in inducing death of cultured cortical neurons prepared from WT and ASIC1a-knockout mice. 3,23 We found that ASIC1a gene deletion significantly protected neurons against .…”

“…1 Homomeric ASIC1a channels are expressed throughout central and peripheral nervous systems and are implicated in learning/memory, pain sensation and neuronal death. [1][2][3][4][5][6][7][8] Among all these functions, mediating ischemic neuronal death was one of the most prominent pathological features of ASIC1a channels. [5][6][7] Although it has been established that severe extracellular acidosis in ischemic brain overactivated ASIC1a and caused neuronal death, 5,6 the death mechanisms remained largely unknown particularly considering that ASIC1a channels completely desensitize within a few seconds during persistent acidosis.…”

“…[1][2][3][4][5][6][7][8] Among all these functions, mediating ischemic neuronal death was one of the most prominent pathological features of ASIC1a channels. [5][6][7] Although it has been established that severe extracellular acidosis in ischemic brain overactivated ASIC1a and caused neuronal death, 5,6 the death mechanisms remained largely unknown particularly considering that ASIC1a channels completely desensitize within a few seconds during persistent acidosis. 9 Thus, under such ischemic conditions, there might be other ASIC1a-associated mechanism(s) than acidosisinduced channel activation to explain the prominent effect against ischemic insult in the ASIC1a gene deletion mutant.…”

Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus

“…Several studies highlight a role of ASIC1a in different physiological conditions including synaptic plasticity, learning and memory, transmission of nerve impulses as well as in pathological settings such as ischemia, neuronal injury and epilepsy [8,[13][14][15]. It has been demonstrated that ASICs are required for long-term potentiation (LTP) at cortico-basal lateral amygdala synapses, and are critical for associative fear learning and memory [16].…”