Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines.
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ABSTRACT:
SUBMITTER: Zha XM
PROVIDER: S-EPMC1621052 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The entry of calcium into dendritic spines can trigger a sequence of biochemical reactions that begins with the activation of calmodulin (CaM) and ends with long-term changes to synaptic strengths. The degree of activation of CaM can depend on highly local elevations in the concentration of calcium and the duration of transient increases in calcium concentration. Accurate measurement of these local changes in calcium is difficult because the spaces are so small and the numbers of molecules are so low. We have therefore developed a Monte Carlo model of intracellular calcium dynamics within the spine that included calcium binding proteins, calcium transporters and ion channels activated by voltage and glutamate binding. The model reproduced optical recordings using calcium indicator dyes and showed that without the dye the free intracellular calcium concentration transient was much higher than predicted from the fluorescent signal. Excitatory postsynaptic potentials induced large, long-lasting calcium gradients across the postsynaptic density, which activated CaM. When glutamate was released at the synapse 10 ms before an action potential occurred, simulating activity patterns that strengthen hippocampal synapses, the calcium gradient and activation of CaM in the postsynaptic density were much greater than when the order was reversed, a condition that decreases synaptic strengths, suggesting a possible mechanism underlying the induction of long-term changes in synaptic strength. The spatial and temporal mechanisms for selectivity in CaM activation demonstrated here could be used in other signaling pathways.
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Project description:Acid-sensing ion channels (ASICs) are proton-gated cation channels that exist throughout the mammalian central and peripheral nervous systems. ASIC1 is the most abundant of all the ASICs and is likely to modulate synaptic transmission. Identifying the proton-binding sites of ASCI1 is required to elucidate its pH-sensing mechanism. By using the crystal structure of ASIC1, the protonation states of each titratable site of ASIC1 were calculated by solving the Poisson-Boltzmann equation under conditions wherein the protonation states of all these sites are simultaneously in equilibrium. Four acidic-acidic residue pairs--Asp238-Asp350, Glu220-Asp408, Glu239-Asp346, and Glu80-Glu417--were found to be highly protonated. In particular, the Glu80-Glu417 pair in the inner pore was completely protonated and possessed 2 H(+), implying its possible importance as a proton-binding site. The pK(a) of Glu239, which forms a pair with a possible pH-sensing site Asp346, differs among each homo-trimer subunit due to the different H-bond pattern of Thr237 in the different protein conformations of the subunits. His74 possessed a pK(a) of ?6-7. Conservation of His74 in the proton-sensitive ASIC3 that lacks a residue corresponding to Asp346 may suggest its possible pH-sensing role in proton-sensitive ASICs.
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Project description:Acid-sensing ion channels (ASICs) are voltage-independent Na(+) channels activated by extracellular protons. ASIC1a is expressed in neurons in mammalian brain and is implicated in long term potentiation of synaptic transmission that contributes to learning and memory. In ischemic brain injury, however, activation of this Ca(2+)-permeable channel plays a critical role in acidosis-mediated, glutamate-independent, Ca(2+) toxicity. We report here the identification of insulin as a regulator of ASIC1a surface expression. In modeled ischemia using Chinese hamster ovary cells, serum depletion caused a significant increase in ASIC1a surface expression that resulted in the potentiation of ASIC1a activity. Among the components of serum, insulin was identified as the key factor that maintains a low level of ASIC1a on the plasma membrane. Neurons subjected to insulin depletion increased surface expression of ASIC1a with resultant potentiation of ASIC1a currents. Intracellularly, ASIC1a is predominantly localized to the endoplasmic reticulum in Chinese hamster ovary cells, and this intracellular localization is also observed in neurons. Under conditions of serum or insulin depletion, the intracellular ASIC1a is translocated to the cell surface, increasing the surface expression level. These results reveal an important trafficking mechanism of ASIC1a that is relevant to both the normal physiology and the pathological activity of this channel.
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Project description:The action of extracellular protons on retinal activity and phototransduction occurs through pH-sensitive elements, mainly membrane conductances present on the different cell types of the outer and inner nuclear layers and of the ganglion cell layer. Acid-sensing ion channels (ASICs) are depolarizing conductances that are directly activated by protons. We investigated the participation of ASIC1a, a particular isoform of ASICs, in retinal physiology in vivo using electroretinogram measurements. In situ hybridization and immunohistochemistry localized ASIC1a in the outer and inner nuclear layers (cone photoreceptors, horizontal cells, some amacrine and bipolar cells) and in the ganglion cell layer. Both the in vivo knockdown of ASIC1a by antisense oligonucleotides and the in vivo blocking of its activity by PcTx1, a specific venom peptide, were able to decrease significantly and reversibly the photopic a- and b-waves and oscillatory potentials. Our study indicates that ASIC1a is an important channel in normal retinal activity. Being present in the inner segments of cones and inner nuclear layer cells, and mainly at synaptic cleft levels, it could participate in gain adaptation to ambient light of the cone pathway, facilitating cone hyperpolarization in brightness and modulating synaptic transmission of the light-induced visual signal.
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Project description:Acid-sensing ion channels are cation channels activated by external protons and play roles in nociception, synaptic transmission, and the physiopathology of ischemic stroke. Using luminescence resonance energy transfer (LRET), we show that upon proton binding, there is a conformational change that increases LRET efficiency between the probes at the thumb and finger subdomains in the extracellular domain of acid-sensing ion channels. Additionally, we show that this conformational change is lost upon mutating Asp-238, Glu-239, and Asp-260, which line the finger domains, to alanines. Electrophysiological studies showed that the single mutant D260A shifted the EC50 by 0.2 pH units, the double mutant D238A/E239A shifted the EC50 by 2.5 pH units, and the triple mutant D238A/E239A/D260A exhibited no response to protons despite surface expression. The LRET experiments on D238A/E239A/D260A showed no changes in LRET efficiency upon reduction in pH from 8 to 6. The LRET and electrophysiological studies thus suggest that the three carboxylates, two of which are involved in carboxyl/carboxylate interactions, are essential for proton-induced conformational changes in the extracellular domain, which in turn are necessary for receptor activation.
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Project description: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 small-amplitude 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.
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Project description:Acid-sensing ion channels (ASICs) are trimeric proton-gated sodium channels. Recently it has been shown that these channels play a role in necroptosis following prolonged acidic exposure like occurs in stroke. The C-terminus of the channel is thought to mediate necroptotic cell death through interaction with receptor interacting serine threonine kinase 1 (RIPK1). This interaction is suggested to be inhibited at rest via an interaction between the C-terminus and the N-terminus which blocks the RIPK1 binding site. Here, we use a combination of two transition metal ion FRET (tmFRET) methods to investigate the conformational dynamics of the termini while the channel is closed and desensitized. We do not find evidence that the termini are close enough to be bound while the channel is at rest and find that the termini may modestly move closer together when desensitized. At rest, the N-terminus adopts a conformation parallel to the membrane about 10 Å away. The C-terminus, including the distal end, may also spend time close to the membrane at rest. After prolonged acidification, the proximal portion of the N-terminus moves marginally closer to the membrane whereas the distal portion of the C-terminus swings away from the membrane. Together these data suggest that a new hypothesis for RIPK1 binding during stroke is needed.
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Project description:Acid-sensing ion channels (ASICs) are trimeric proton-gated sodium channels. Recent work has shown that these channels play a role in necroptosis following prolonged acidic exposure like occurs in stroke. The C-terminus of ASIC1a is thought to mediate necroptotic cell death through interaction with receptor interacting serine threonine kinase 1 (RIPK1). This interaction is hypothesized to be inhibited at rest via an interaction between the C- and N-termini which blocks the RIPK1 binding site. Here, we use two transition metal ion FRET methods to investigate the conformational dynamics of the termini at neutral and acidic pH. We do not find evidence that the termini are close enough to be bound while the channel is at rest and find that the termini may modestly move closer together during acidification. At rest, the N-terminus adopts a conformation parallel to the membrane about 10 Å away. The distal end of the C-terminus may also spend time close to the membrane at rest. After acidification, the proximal portion of the N-terminus moves marginally closer to the membrane whereas the distal portion of the C-terminus swings away from the membrane. Together these data suggest that a new hypothesis for RIPK1 binding during stroke is needed.
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Project description:Structural plasticity of dendritic spines is thought to underlie memory formation. Size of a dendritic spine is considered proportional to the size of its postsynaptic density (PSD), number of glutamate receptors and synaptic strength. However, whether this correlation is true for all dendritic spine volumes, and remains stable during synaptic plasticity, is largely unknown. In this study, we take advantage of 3D electron microscopy and reconstruct dendritic spines and cores of PSDs from the stratum radiatum of the area CA1 of organotypic hippocampal slices. We observe that approximately 1/3 of dendritic spines, in a range of medium sizes, fail to reach significant correlation between dendritic spine volume and PSD surface area or PSD-core volume. During NMDA receptor-dependent chemical long-term potentiation (NMDAR-cLTP) dendritic spines and their PSD not only grow, but also PSD area and PSD-core volume to spine volume ratio is increased, and the correlation between the sizes of these two is tightened. Further analysis specified that only spines that contain smooth endoplasmic reticulum (SER) grow during cLTP, while PSD-cores grow irrespectively of the presence of SER in the spine. Dendritic spines with SER also show higher correlation of the volumetric parameters than spines without SER, and this correlation is further increased during cLTP only in the spines that contain SER. Overall, we found that correlation between PSD surface area and spine volume is not consistent across all spine volumes, is modified and tightened during synaptic plasticity and regulated by SER.
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Project description:Acid-sensing ion channels (ASICs) are proton-gated sodium-selective channels that are expressed in the peripheral and central nervous systems. ASIC1a is one of the most intensively studied isoforms due to its importance and wide representation in organisms, but it is still largely unexplored as a target for therapy. In this study, we demonstrated response of the ASIC1a to acidification in the presence of the daurisoline (DAU) ligand. DAU alone did not activate the channel, but in combination with protons, it produced the second peak component of the ASIC1a current. This second peak differs from the sustained component (which is induced by RF-amide peptides), as the second (DAU-induced) peak is completely desensitized, with the same kinetics as the main peak. The co-application of DAU and mambalgin-2 indicated that their binding sites do not overlap. Additionally, we found an asymmetry in the pH activation curve of the channel, which was well-described by a mathematical model based on the multiplied probabilities of protons binding with a pool of high-cooperative sites and a single proton binding with a non-cooperative site. In this model, DAU targeted the pool of high-cooperative sites and, when applied with protons, acted as an inhibitor of ASIC1a activation. Moreover, DAU's occupation of the same binding site most probably reverses the channel from steady-state desensitization in the pH 6.9-7.3 range. DAU features disclose new opportunities in studies of ASIC structure and function.
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