Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation

Kweon, Hae-Jin; Suh, Byung‐Chang

doi:10.5483/bmbrep.2013.46.6.121

Cited by 94 publications

(75 citation statements)

References 109 publications

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“…It is known that the local extracellular pH levels drop to 5.4 in acute inflammation and 6.3 or lower in severe ischemia [13,14]. The released protons can cause pain through activating protongated ion channels on peripheral sensory afferents.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons

Ren

Gan

et al. 2015

Purinergic Signalling

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Peripheral purinergic signaling plays an important role in nociception. Increasing evidence suggests that metabotropic P2Y receptors are also involved, but little is known about the underlying mechanism. Herein, we report that selective P2Y receptor agonist uridine 5′-triphosphate (UTP) can exert an enhancing effect on the functional activity of acidsensing ion channels (ASICs), key sensors for extracellular protons, in rat dorsal root ganglia (DRG) neurons. First, UTP dose-dependently increased the amplitude of ASIC currents. UTP also shifted the concentration-response curve for proton upwards, with a 56.6±6.4 % increase of the maximal current response to proton. Second, UTP potentiation of proton-gated currents can be mimicked by adenosine 5′-triphosphate (ATP), but not by P2Y1 receptor agonist ADP. Potentiation of UTP was blocked by P2Y receptor antagonist suramin and by inhibition of intracellular G protein, phospholipase C (PLC), protein kinase C (PKC), or protein interacting with C-kinase 1 (PICK1) signaling. Third, UTP altered acidosis-evoked membrane excitability of DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, UTP dose-dependently exacerbated nociceptive responses to injection of acetic acid in rats. These results suggest that UTP enhanced ASIC-mediated currents and nociceptive responses, which reveal a novel peripheral mechanism underlying UTP-sensitive P2Y 2 receptor involvement in hyperalgesia by sensitizing ASICs in primary sensory neurons.

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Section: Introductionmentioning

confidence: 99%

Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons

Ren

Gan

et al. 2015

Purinergic Signalling

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“…Provocative evidence has demonstrated that ASICs, which are known to be activated by extracellular H ϩ , are novel targets for ischemic stroke therapy (51)(52)(53). In contrast to the decrease in extracellular pH with focal ischemia, intracellular pH changes and specifically an increase of intracellular pH have been reported in many studies (27,29,31,32,54).…”

Section: Discussionmentioning

confidence: 99%

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

Leng

Feng

et al. 2016

Journal of Biological Chemistry

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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...

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“…These toxins, as well as a toxin from the Texas coral snake (Micrurus tener tener) known as MitTx, are of interest because they belong to a family of toxins that specically affect acid-sensing ion channels (ASICs), which are key mediators of inammatory pain. 190 MitTx, however, induces hyperalgesia in animals. 191 Because these toxins affect ASICs, they hold the potential for development as analgesics targeting many different localized types of pain.…”

Section: Analgesicsmentioning

confidence: 97%

CHAPTER 5. Reptile Venoms as a Platform for Drug Development

McCleary¹,

Kang²,

Kini³

2015

Drug Discovery

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Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation

Cited by 94 publications

References 109 publications

Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons

Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons

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

CHAPTER 5. Reptile Venoms as a Platform for Drug Development

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