Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels

Chu, Xiang‐Ping; Wemmie, John A.; Wang, Wei Zhen; Zhu, Xiao Man; Saugstad, Julie A.; Price, Margaret P.; Simon, Roger P.; Xiong, Zhi Gang

doi:10.1523/jneurosci.2844-04.2004

Cited by 147 publications

(174 citation statements)

References 87 publications

(109 reference statements)

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“…Interestingly, expression of rat ASIC3 in Xenopus oocytes (Babinski et al, 2000;Benson et al, 2002) demonstrated a lowerproton sensitivity compared with mammalian expression systems (Benson et al, 2002), suggesting that other associated subunits may be involved in modifying properties of acid-sensitive currents. To further evaluate the subunit composition of native ASIC channels expressed in gastric sensory neurons, we examined effects of two known modulators: Zn 2ϩ and TPEN, a positive and negative modulator of ASIC2a and ASIC1a subunits, respectively (Baron et al, 2001;Chu et al, 2004). Although Zn 2ϩ had no effect in some cells, consistent with previous findings reported for hippocampal and cortical neurons Chu et al, 2004), Zn 2ϩ significantly increased the proton- neurons.…”

Section: Asics and Gastric Sensory Neuronssupporting

confidence: 71%

“…To further evaluate the subunit composition of native ASIC channels expressed in gastric sensory neurons, we examined effects of two known modulators: Zn 2ϩ and TPEN, a positive and negative modulator of ASIC2a and ASIC1a subunits, respectively (Baron et al, 2001;Chu et al, 2004). Although Zn 2ϩ had no effect in some cells, consistent with previous findings reported for hippocampal and cortical neurons Chu et al, 2004), Zn 2ϩ significantly increased the proton- neurons. An initial 10 s exposure to acid for complete desensitization (filled bar; pH 6.8 in DRG neurons and pH 5.5 in NG neurons) was followed by a second, 2 s test stimulus at the same pH at varying interstimulus intervals (unfilled bars).…”

Section: Asics and Gastric Sensory Neuronssupporting

confidence: 71%

“…4C,D) had no effects on the fast desensitizing and sustained currents in seven gastric NG neurons tested (108 Ϯ 10 and 112 Ϯ 7% of control for fast desensitizing and sustained component, respectively; NS). Similarly, the Zn 2ϩ chelator TPEN, which potentiates ASIC1a-containing channels (Chu et al, 2004), had discordant effects on slowly desensitizing currents in DRG neurons, increasing peak currents in 9 of 26 neurons to 330 Ϯ 80% of control ( p Ͻ 0.05) while decreasing currents in six neurons to 53 Ϯ 16% of control ( p Ͻ 0.05). TPEN did not affect currents in the remaining 11 neurons.…”

Section: Pharmacological Properties Of Acid-sensitive Currentsmentioning

confidence: 98%

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Acid-Sensing Properties in Rat Gastric Sensory Neurons from Normal and Ulcerated Stomach

Sugiura¹,

Dang²,

Lamb³

et al. 2005

J. Neurosci.

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Section: Asics and Gastric Sensory Neuronssupporting

confidence: 71%

Section: Asics and Gastric Sensory Neuronssupporting

confidence: 71%

Section: Pharmacological Properties Of Acid-sensitive Currentsmentioning

confidence: 98%

See 1 more Smart Citation

Acid-Sensing Properties in Rat Gastric Sensory Neurons from Normal and Ulcerated Stomach

Sugiura¹,

Dang²,

Lamb³

et al. 2005

J. Neurosci.

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“…While this work was in proof, an article showing that Zn 2ϩ inhibits only ASIC1a currents was published (Chu et al, 2003), supporting our case that the ASICIa subunit is the most likely candidate mediating I Na(Hϩ) in RGCs.…”

Section: Physiological Rolesupporting

confidence: 78%

The Discovery and Characterization of a Proton-Gated Sodium Current in Rat Retinal Ganglion Cells

Lilley¹,

Tissier²,

Robbins³

2004

J. Neurosci.

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The conduction of acid-evoked currents in central and sensory neurons is now primarily attributed to a family of proteins called acid-sensing ion channels (ASICs). In peripheral neurons, their physiological function has been linked to nociception, mechanoreception, and taste transduction; however, their role in the CNS remains unclear. This study describes the discovery of a proton-gated current in rat retinal ganglion cells termed I Na(Hϩ) , which also appears to be mediated by ASICs. RT-PCR confirmed the presence of ASIC mRNA (subunits la, 2a, 2b, 3, and 4) in the rat retina. Electrophysiological investigation showed that all retinal ganglion cells respond to rapid extracellular acidification with the activation of a transient Na ϩ current, the size of which increases with increasing acidification between pH 6.5 and pH 3.0. I Na(Hϩ) desensitizes completely in the continued presence of acid, its current-voltage relationship is linear and its reversal potential shifts with E Na . I Na(Hϩ) is reversibly inhibited by amiloride (IC 50 , 188 M) but is resistant to block by TTX (0.5 M), Cd 2ϩ (100 M), procaine (10 mM), and is not activated by capsaicin (0.5 M). I Na(Hϩ) is not potentiated by Zn 2ϩ (300 M) or Phe-MetArg-Phe-amide (50 M) but is inhibited by neuropeptide-FF (50 M). Acute application of pH 6.5 to retinal ganglion cells causes sustained depolarization and repetitive firing similar to the trains of action potentials normally associated with current injection into these cells. The presence of a proton-gated current in the neural retina suggests that ASICs may have a more diverse role in the CNS.

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“…Most modulators of ASIC1a function, including zinc, redox reagents, lactate, and PcTx1, act by altering the apparent proton sensitivity of the channel (16,18,25,(31)(32)(33)(34). These compounds also impact ASIC1a-induced neuronal death (8,9,15,31).…”

Section: Discussionmentioning

confidence: 99%

Identification of Protein Domains That Control Proton and Calcium Sensitivity of ASIC1a

Sherwood

Franke

Conneely

et al. 2009

Journal of Biological Chemistry

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The acid-sensing ion channels (ASICs) open in response to extracellular acidic pH, and individual subunits display differential sensitivity to protons and calcium. ASIC1a acts as a high affinity proton sensor, whereas ASIC2a requires substantially greater proton concentrations to activate. Using chimeras composed of ASIC1a and ASIC2a, we determined that two regions of the extracellular domain (residues 87-197 and 323-431) specify the high affinity proton response of ASIC1a. These two regions appear to undergo intersubunit interactions within the multimeric channel to specify proton sensitivity. Single amino acid mutations revealed that amino acids around Asp 357 play a prominent role in determining the pH dose response of ASIC1a. Within the same region, mutation F352L abolished PcTx1 modulation of ASIC1a. Surprisingly, we determined that another area of the extracellular domain was required for calcium-dependent regulation of ASIC1a activation, and this region functioned independently of high affinity proton sensing. These results indicate that specific regions play overlapping roles in pH-dependent gating and PcTx1-dependent modulation of ASIC1a activity, whereas a distinct region determines the calcium dependence of ASIC1a activation.The acid-sensing ion channels (ASICs) 3 are proton-gated ion channels expressed in neurons throughout the central and peripheral nervous system (1-3). ASICs are activated by extracellular acidosis, and protons act as ligands triggering channel opening (4). Disruption of the accn2 gene (which encodes ASIC1) dramatically reduces proton-gated currents in central neurons and alters a variety of behaviors, including fear, learning, and memory (5, 6). ASIC1 also contributes to neuronal damage and death during the prolonged acidosis accompanying cerebral ischemia (7). Specifically, mice with disruptions in the accn2 gene display 60% smaller lesion size compared with normal mice in models of stroke (8). Application of PcTx1, a venom peptide that prevents ASIC1a activation, is similarly neuroprotective, even when administered hours after injury (8, 9). Thus, ASIC1a represents a novel pharmacological target for the prevention of neuronal death following stroke.Mammals have four genes encoding ASICs (accn1 to -4) that encode at least six different ASIC subunits (1-3, 10). Like all members of the DEG/ENaC family, individual ASIC subunits have two transmembrane regions separated by a large cysteinerich extracellular region. Three ASIC subunits associate to form homomeric or heteromeric channels with distinct biophysical characteristics (11)(12)(13)(14). Specifically, ASIC1a homomeric channels activate at pH values much closer to neutral pH compared with ASIC2a homomeric channels. The high affinity proton sensitivity of ASIC1a plays a prominent role in acidosisinduced neuronal death, and modulators that alter the pH dose response of ASIC1a affect neuronal sensitivity to prolonged acidosis (8, 9, 15). For example, the neuroprotective venom peptide PcTx1 increases the proton sensitivity of the ...

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Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels

Cited by 147 publications

References 87 publications

Acid-Sensing Properties in Rat Gastric Sensory Neurons from Normal and Ulcerated Stomach

Acid-Sensing Properties in Rat Gastric Sensory Neurons from Normal and Ulcerated Stomach

The Discovery and Characterization of a Proton-Gated Sodium Current in Rat Retinal Ganglion Cells

Identification of Protein Domains That Control Proton and Calcium Sensitivity of ASIC1a

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