Modulation of Acid-sensing Ion Channel 1a by Intracellular pH and Its Role in Ischemic Stroke

Abstract

An important contributor to brain ischemia is known to be extracellular acidosis, which activates acid-sensing ion channels (ASICs), a family of proton-gated sodium channels. Lines of evidence suggest that targeting ASICs may lead to novel therapeutic strategies for stroke. Investigations of the role of ASICs in ischemic brain injury have naturally focused on the role of extracellular pH in ASIC activation. By contrast, intracellular pH (pH i ) has received little attention. This is a significant gap in our understanding because the ASIC response to extracellular pH is modulated by pH i , and activation of ASICs by extracellular protons is paradoxically enhanced by intracellular alkalosis. Our previous studies show that acidosis-induced cell injury in in vitro models is attenuated by intracellular acidification. However, whether pH i affects ischemic brain injury in vivo is completely unknown. Furthermore, whereas ASICs in native neurons are composed of different subunits characterized by distinct electrophysiological/pharmacological properties, the subunit-dependent modulation of ASIC activity by pH i has not been investigated. Using a combination of in vitro and in vivo ischemic brain injury models, electrophysiological, biochemical, and molecular biological approaches, we show that the intracellular alkalizing agent quinine potentiates, whereas the intracellular acidifying agent propionate inhibits, oxygen-glucose deprivation-induced cell injury in vitro and brain ischemiainduced infarct volume in vivo. Moreover, we find that the potentiation of ASICs by quinine depends on the presence of the ASIC1a, ASIC2a subunits, but not ASIC1b, ASIC3 subunits. Furthermore, we have determined the amino acids in ASIC1a that are involved in the modulation of ASICs by pH i .A common feature of brain ischemia is acidosis (1-5), which plays a critical role in the ensuing brain injury. However, the mechanisms of acidosis-induced injury remain poorly understood. Acidosis activates acid-sensing ion channels (ASICs), 4 a family of proton-gated cation channels that belong to the degenerin and epithelial Na ϩ channel superfamily of ion channels (6). These channels are expressed in neurons throughout the peripheral and central nervous systems (6 -9). In sensory neurons, ASICs play important roles in nociception (9 -11), mechanosensation (12, 13), and taste transduction (14), whereas in the central nervous system (CNS), ASICs are involved in processes such as synaptic plasticity, learning, and memory (15-17). The specific ASIC important in acidosis-induced injury is the ASIC1a subtype (5, 18). This subtype has a higher sensitivity to protons and is both sodium-and calciumpermeable. Neuronal injury induced by ASIC activation is independent of glutamate receptor-mediated excitotoxicity (5, 18), offering provocative new evidence for ASICs as potential new targets for stroke therapy (4, 5, 19 -21).In the brain, energy is stored mainly in the form of the high energy phosphate compound ATP. In normoxia, ATP is predominantly produced by oxid...

Cathepsins: Proteases that are vital for survival but can also be fatal

“…Acidosis induces MAPK (mitogen-activated protein kinase) phosphorylation [101], and activates proton-sensing proteins (G-protein-coupled receptor (GPCR) as OGR1, GPR4, and TDAG8) which impedes actin polymerization/depolymerization [102,103]. Ion channels as the proton-gated sodium channels are manipulated, and the ionic perturbation leads to pain [104][105][106]. Perceiving that stressors are around, efflux proteins such as P-glycoprotein (P-gp) are expressed [107][108][109][110].…”

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

“…For instance, anaerobic conditions of ischemia promote the alteration of the metabolism of the cells from aerobic oxidation of glucose to anaerobic glycolysis. This alteration in metabolism produces lactate and protons, which is responsible for acidosis (Li et al, 2016). Interestingly, a curious phenomenon occurs in acidosis.…”

Acid‐sensing ion channel 1a is involved in ischaemia/reperfusion induced kidney injury by increasing renal epithelia cell apoptosis

“…Accumulating evidence demonstrated that ASICs participate in pathological progress of various organs such as brain, retinal, heart and articular cartilage ischaemic injuries. [17][18][19][20] ASIC1a a Ca 2+ -permeable ASICs subunit serve as novel targets for ischaemic stroke therapy. 8…”