Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala

Du, Jianyang; Reznikov, Leah R.; Price, Margaret P.; Zha, Xiang-ming; Lü, Yuan; Moninger, Thomas O.; Wemmie, John A.; Welsh, Michael J.

doi:10.1073/pnas.1407018111

Cited by 244 publications

(380 citation statements)

References 51 publications

(67 reference statements)

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“…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 allosteric modulators is a promising therapeutic objective (15-17).Acid-sensing ion channels (ASICs) have recently been shown to act as NGICs (18,19). In both the lateral amygdala (18) and the nucleus accumbens (19), the brief acidification of the synaptic cleft accompanying neurotransmission can activate postsynaptic ASICs that contribute to EPSCs.…”

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confidence: 99%

“…A pH drop of 0.2-0.6 pH units or greater can accompany single-release events, but the synaptic cleft pH may not return directly back to physiological pH (21-25). Rather, following brief stimulations, synaptic cleft pH "overshoots" the physiological range by 0.2 pH units or more and remains alkaline for several tens or hundreds of milliseconds (18,(26)(27)(28). Cleft pH can also remain persistently acidic during prolonged bouts of activity, during stimulation, or during a variety of pathological conditions such as spreading depression or epileptic activity (27,29,30).…”

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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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confidence: 99%

mentioning

confidence: 99%

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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“…The idea that protons can function as a neurotransmitter has existed for some time [35][36][37], however the precise role of ASICs in synaptic transmission and neuroplasticity remains still elusive [16,[37][38][39]. In fact, it has been suggested that ASIC1a may contribute to certain forms of synaptic plasticity in the hippocampus, although results are controversial [8,17,18].…”

Section: Discussionmentioning

confidence: 99%

“…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]. On the other hand, the role of ASICs in the hippocampus is still not clear [8,13,17,18] and may vary depending on the experimental conditions used.…”

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confidence: 99%

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

Mango

Braksator

Battaglia

et al. 2017

Pharmacological Research

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a b s t r a c tAcid-sensing ion channels (ASICs), members of the degenerin/epithelial Na + channel superfamily, are widely distributed in the mammalian nervous system. ASIC1a is highly permeable to Ca 2+ and are thought to be important in a variety of physiological processes, including synaptic plasticity, learning and memory. To further understand the role of ASIC1a in synaptic transmission and plasticity, we investigated metabotropic glutamate (mGlu) receptor-dependent long-term depression (LTD) in the hippocampus. We found that ASIC1a channels mediate a component of LTD in P30-40 animals, since the ASIC1a selective blocker psalmotoxin-1 (PcTx1) reduced the magnitude of LTD induced by application of the group I mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) or induced by paired-pulse low frequency stimulation (PP-LFS). Conversely, PcTx1 did not affect LTD in P13-18 animals. We also provide evidence that ASIC1a is involved in group I mGlu receptor-induced increase in action potential firing. However, blockade of ASIC1a did not affect DHPG-induced polyphosphoinositide hydrolysis, suggesting the involvement of some other molecular partners in the functional crosstalk between ASIC1a and group I mGlu receptors. Notably, PcTx1 was able to prevent the increase in GluA1 S845 phosphorylation at the post-synaptic membrane induced by group I mGlu receptor activation. These findings suggest a novel function of ASIC1a channels in the regulation of group I mGlu receptor synaptic plasticity and intrinsic excitability.

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“…ASICs are mainly neuronal channels, which are activated by a sudden increase in the extracellular proton concentration (4). They are involved in the sensation of pain and mechanical stimuli, synaptic transmission, and various cognitive processes (5)(6)(7)(8)(9)(10)(11)(12). ENaC is mainly involved in the absorption of Na ϩ in a variety of tissues.…”

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confidence: 99%

A Cytosolic Amphiphilic α-Helix Controls the Activity of the Bile Acid-sensitive Ion Channel (BASIC)

Schmidt

Löhrer

Alsop

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanThe bile acid-sensitive ion channel (BASIC) is a member of the degenerin/epithelial Na ؉ channel (Deg/ENaC) family of ion channels. It is mainly found in bile duct epithelial cells, the intestinal tract, and the cerebellum and is activated by alterations of its membrane environment. Bile acids, one class of putative physiological activators, exert their effect by changing membrane properties, leading to an opening of the channel. The physiological function of BASIC, however, is unknown. Deg/ ENaC channels are characterized by a trimeric subunit composition. Each subunit is composed of two transmembrane segments, which are linked by a large extracellular domain. The termini of the channels protrude into the cytosol. Many Deg/ ENaC channels contain regulatory domains and sequence motifs within their cytosolic domains. In this study, we show that BASIC contains an amphiphilic ␣-helical structure within its N-terminal domain. This ␣-helix binds to the cytosolic face of the plasma membrane and stabilizes a closed state. Truncation of this domain renders the channel hyperactive. Collectively, we identify a cytoplasmic domain, unique to BASIC, that controls channel activity via membrane interaction.

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Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala

Cited by 244 publications

References 51 publications

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

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

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

A Cytosolic Amphiphilic α-Helix Controls the Activity of the Bile Acid-sensitive Ion Channel (BASIC)

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