Independent Contribution of Extracellular Proton Binding Sites to ASIC1a Activation

Krauson, Aram J.; Rued, Anna C.; Carattino, Marcelo D.

doi:10.1074/jbc.m113.504324

Cited by 50 publications

(65 citation statements)

References 26 publications

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“…Mutagenesis studies have indeed shown that residues of the acidic pocket together with protonatable residues in other domains such as, for example the palm, co-determine the pH dependence of ASICs (6,12,13,31,32). So far the only experimental indication for conformational changes in the acidic pocket comes from an observation by VCF suggesting that E355C moves during desensitization to a less exposed position, consistent with a closing of the acidic pocket (14).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Subunit Interactions Control Transitions between Functional States of Acid-sensing Ion Channel 1a

Gwiazda

Bonifacio

Vullo

et al. 2015

Journal of Biological Chemistry

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Background: It is currently not known how extracellular interaction surfaces between ASIC subunits change during channel activity. Results: Different engineered extracellular intersubunit disulfide bonds lock ASIC1a in open or non-conducting states. Conclusion: Subunit interactions are critical for the ASIC gating process. Significance: This study highlights new features of the mechanisms by which the pH controls ASIC activity.

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Section: Discussionmentioning

confidence: 99%

Extracellular Subunit Interactions Control Transitions between Functional States of Acid-sensing Ion Channel 1a

Gwiazda

Bonifacio

Vullo

et al. 2015

Journal of Biological Chemistry

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“…Such a model not only accounts for rapid deactivation at pH 8, markedly slower deactivation at pH 7, and the appropriate pH response curve but also harmonizes with existing structural data. Proton activation is thought to proceed from protons binding to pairs of carboxylate residues in the acidic pocket formed by the thumb and finger (53)(54)(55) may also arise from similar pairs in the palm domain (56,57) or elsewhere (60,61). In both regions, carboxylate residues are in close apposition.…”

Section: Discussionmentioning

confidence: 99%

“…Protonation of these residues brings the thumb and finger domain close together in a motion correlated with activation/desensitization (55). In the palm domain, protonation of E79 and E416 appears to be important, because neutralizing these positions left shifts dose-response curves and incorporating MTS reagents produces bell-shaped doseresponse curves (57). We therefore neutralized each of these positions in turn and examined the effect on the pH dependence of deactivation.…”

Section: Mutations To Putative Proton Sensors Attenuate Ph-dependentmentioning

confidence: 99%

“…To attenuate cooperativity we set out to remove some of ASICs' proton sensors. ASICs are known to have at least two distinct regions of acidic residues implicated in gating (53)(54)(55)(56)(57): the "acidic pocket" formed at interface between the finger and thumb domains as well as the palm domain (Fig. 7A).…”

Section: Mutations To Putative Proton Sensors Attenuate Ph-dependentmentioning

confidence: 99%

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Deactivation kinetics of acid-sensing ion channel 1a are strongly pH-sensitive

MacLean

Jayaraman

2017

Proc. Natl. Acad. Sci. U.S.A.

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Acid-sensing ion channels (ASICs) are trimeric cation-selective ion channels activated by protons in the physiological range. Recent reports have revealed that postsynaptically localized ASICs contribute to the excitatory postsynaptic current by responding to the transient acidification of the synaptic cleft that accompanies neurotransmission. In response to such brief acidic transients, both recombinant and native ASICs show extremely rapid deactivation in outside-out patches when jumping from a pH 5 stimulus to a single resting pH of 8. Given that the resting pH of the synaptic cleft is highly dynamic and depends on recent synaptic activity, we explored the kinetics of ASIC1a and 1a/2a heteromers to such brief pH transients over a wider [H + ] range to approximate neuronal conditions better. Surprisingly, the deactivation of ASICs was steeply dependent on the pH, spanning nearly three orders of magnitude from extremely fast (<1 ms) at pH 8 to very slow (>300 ms) at pH 7. This study provides an example of a ligand-gated ion channel whose deactivation is sensitive to agonist concentrations that do not directly activate the receptor. Kinetic simulations and further mutagenesis provide evidence that ASICs show such steeply agonist-dependent deactivation because of strong cooperativity in proton binding. This capacity to signal across such a large synaptically relevant bandwidth enhances the response to smallamplitude acidifications likely to occur at the cleft and may provide ASICs with the ability to shape activity in response to the recent history of the synapse.acid-sensing ion channel | gating | kinetics | ligand-gated ion channel N eurotransmitter levels within the synaptic cleft rise and fall very rapidly, with clearance times generally on the order of a few hundred microseconds to 2 ms (1-3). However, the duration of responses from neurotransmitter-gated ion channels (NGICs) varies widely across several orders of magnitude depending on the receptors involved. For example, in certain regions, glutamatergic excitatory postsynaptic currents (EPSCs) decay with submillisecond time constants (4), but the EPSCs of GluN2D-containing NMDA receptors decay over roughly 200 ms (5, 6). Such differences in the decay or deactivation of NGIC responses can profoundly impact the window of synaptic excitability and integration (4,7,8). Control over NGIC kinetics is also a powerful force during development, where slower receptor subtypes tend to be used early on, broadening the window of plasticity during critical periods, and later give way to faster decaying subunits providing greater temporal precision (9-13). This trade-off between the window of integration on the one hand and temporal precision on the other persists in the mature brain. There, synapses host an NGIC compliment kinetically suited to their input patterns (14) but are also capable of dynamically shifting between the priorities of integration and precision (8). Unsurprisingly then, influencing the deactivation kinetics of specific NGIC subtypes using allosteri...

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“…A major challenge in elucidating ENaC gene family function has been the ability to distinguish ligand binding from downstream transduction steps. The crystal structure of ASIC1 suggests several putative proton binding sites, and mutations at select sites affect acid activation of ASIC1 (17)(18)(19). However, one cannot readily distinguish a proton binding site from sites involved in transmitting conformational changes to the channel gate.…”

mentioning

confidence: 99%

Na+ Inhibits the Epithelial Na+ Channel by Binding to a Site in an Extracellular Acidic Cleft

Kashlan

Blobner

Zuzek

et al. 2015

Journal of Biological Chemistry

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Independent Contribution of Extracellular Proton Binding Sites to ASIC1a Activation

Cited by 50 publications

References 26 publications

Extracellular Subunit Interactions Control Transitions between Functional States of Acid-sensing Ion Channel 1a

Extracellular Subunit Interactions Control Transitions between Functional States of Acid-sensing Ion Channel 1a

Deactivation kinetics of acid-sensing ion channel 1a are strongly pH-sensitive

Na+ Inhibits the Epithelial Na+ Channel by Binding to a Site in an Extracellular Acidic Cleft

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