scholarly journals Divergent functional and conformational outcomes in an ion channel-peptide interaction

2021 ◽  
Author(s):  
Christian Bernsen Borg ◽  
Stephanie Andrea Heusser ◽  
Janne Colding ◽  
Stephan Alexander Pless
Keyword(s):  
Ion Channels ◽  
Synaptic Transmission ◽  
Ion Channel ◽  
Extracellular Domain ◽  
Cation Channels ◽  
Precise Control ◽  
Acid Sensing Ion Channels ◽  
Subunit Interface ◽  
Ligand Interactions ◽  
Peptide Interaction

Acid-sensing ion channels (ASICs) are trimeric proton-gated cation channels that contribute to fast synaptic transmission. Pharmacological inhibition of ASIC1a has been shown to reduce neurotoxicity and infarct volumes during stroke. The cysteine knot toxin Psalmotoxin-1 (PcTx1) is one of the most potent and selective inhibitors of ASIC1a. PcTx1 binds at the subunit interface, but both the stoichiometric requirements and the dynamics of the conformational consequences of the ion channel-peptide interaction remain unknown. Here, we use a combination of electrophysiology, voltage-clamp fluorometry and subunit concatenation to decipher the mechanism of PcTx1 inhibition. We observe a long-lived PcTx1-induced conformational change in the ASIC1a extracellular domain that is destabilized by the F350L mutation at the PcTx1 binding site. Concatemeric channel constructs show that two WT ASIC1a subunits are sufficient for WT-like current inhibition, while the presence of a single mutated subunit is enough to destabilize the PcTx1-induced conformation. Our results therefore demonstrate a divergence between the functional effects of PcTx1 on the pore and its conformational consequences in the extracellular domain. It further highlights how engineering of ion channels enables precise control over individual subunits for pharmacological and conformational assessment to determine the mechanism of ion channel-ligand interactions.

scholarly journals The Neuropeptide Nocistatin Is Not a Direct Agonist of Acid-Sensing Ion Channel 1a (ASIC1a)

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 571
Author(s):  
Sven Kuspiel ◽  
Dominik Wiemuth ◽  
Stefan Gründer
Keyword(s):  
Ion Channels ◽  
Synaptic Transmission ◽  
Ion Channel ◽  
Cho Cells ◽  
Xenopus Oocytes ◽  
Ionotropic Receptors ◽  
Bath Solution ◽  
Acid Sensing Ion Channels ◽  
Acidic Peptide

Acid-sensing ion channels (ASICs) are ionotropic receptors that are directly activated by protons. Although protons have been shown to act as a neurotransmitter and to activate ASICs during synaptic transmission, it remains a possibility that other ligands directly activate ASICs as well. Neuropeptides are attractive candidates for alternative agonists of ASICs, because related ionotropic receptors are directly activated by neuropeptides and because diverse neuropeptides modulate ASICs. Recently, it has been reported that the neuropeptide nocistatin directly activates ASICs, including ASIC1a. Here we show that nocistatin does not directly activate ASIC1a expressed in Xenopus oocytes or CHO cells. Moreover, we show that nocistatin acidifies the bath solution to an extent that can fully explain the previously reported activation by this highly acidic peptide. In summary, we conclude that nocistatin only indirectly activates ASIC1a via acidification of the bath solution.

scholarly journals Tarantula toxins use common surfaces for interacting with Kv and ASIC ion channels

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Kanchan Gupta ◽  
Maryam Zamanian ◽  
Chanhyung Bae ◽  
Mirela Milescu ◽  
Dmitriy Krepkiy ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Extracellular Domain ◽  
Voltage Sensor ◽  
Concave Surface ◽  
Voltage Sensing ◽  
Membrane Interaction ◽  
Computational Approaches ◽  
Physical Environments

Tarantula toxins that bind to voltage-sensing domains of voltage-activated ion channels are thought to partition into the membrane and bind to the channel within the bilayer. While no structures of a voltage-sensor toxin bound to a channel have been solved, a structural homolog, psalmotoxin (PcTx1), was recently crystalized in complex with the extracellular domain of an acid sensing ion channel (ASIC). In the present study we use spectroscopic, biophysical and computational approaches to compare membrane interaction properties and channel binding surfaces of PcTx1 with the voltage-sensor toxin guangxitoxin (GxTx-1E). Our results show that both types of tarantula toxins interact with membranes, but that voltage-sensor toxins partition deeper into the bilayer. In addition, our results suggest that tarantula toxins have evolved a similar concave surface for clamping onto α-helices that is effective in aqueous or lipidic physical environments.

Acid-sensing ion channels modulate bladder nociception

2021 ◽  
Vol 321 (5) ◽  
pp. F587-F599
Author(s):  
Nicolas Montalbetti ◽  
Marcelo D. Carattino
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Regulatory Mechanism ◽  
Nociceptive Pathways ◽  
Acid Sensing Ion Channels ◽  
Afferent Terminals

Our study indicates that protons and their cognate acid-sensing ion channel receptors are part of a mechanism that operates at bladder afferent terminals to control their function and that the loss of this regulatory mechanism results in hyperactivation of nociceptive pathways and the development of pain in the setting of chemical-induced cystitis.

scholarly journals Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity

2014 ◽  
Vol 17 (8) ◽  
pp. 1083-1091 ◽  
Author(s):  
Collin J Kreple ◽  
Yuan Lu ◽  
Rebecca J Taugher ◽  
Andrea L Schwager-Gutman ◽  
Jianyang Du ◽  
...  
Keyword(s):  
Ion Channels ◽  
Synaptic Transmission ◽  
Acid Sensing Ion Channels

scholarly journals Interaction of Acid-sensing Ion Channel (ASIC) 1 with the Tarantula Toxin Psalmotoxin 1 is State Dependent

2006 ◽  
Vol 127 (3) ◽  
pp. 267-276 ◽  
Author(s):  
Xuanmao Chen ◽  
Hubert Kalbacher ◽  
Stefan Gründer
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Splice Variant ◽  
Na Channels ◽  
Apparent Affinity ◽  
State Dependent ◽  
Acid Sensing Ion Channels ◽  
Acidic Conditions

Acid-sensing ion channels (ASICs) are Na+ channels gated by extracellular H+. Six ASIC subunits that are expressed in neurons have been characterized. The tarantula toxin psalmotoxin 1 has been reported to potently and specifically inhibit homomeric ASIC1a and has been useful to characterize ASICs in neurons. Recently we have shown that psalmotoxin 1 inhibits ASIC1a by increasing its apparent affinity for H+. However, the mechanism by which PcTx1 increases the apparent H+ affinity remained unclear. Here we show that PcTx1 also interacts with ASIC1b, a splice variant of ASIC1a. However, PcTx1 does not inhibit ASIC1b but promotes its opening; under slightly acidic conditions, PcTx1 behaves like an agonist for ASIC1b. Our results are most easily explained by binding of PcTx1 with different affinities to different states (closed, open, and desensitized) of the channel. For ASIC1b, PcTx1 binds most tightly to the open state, promoting opening, whereas for ASIC1a, it binds most tightly to the open and the desensitized state, promoting desensitization.

scholarly journals Acid-Sensing Ion Channels and Mechanosensation

2021 ◽  
Vol 22 (9) ◽  
pp. 4810
Author(s):  
Nina Ruan ◽  
Jacob Tribble ◽  
Andrew M. Peterson ◽  
Qian Jiang ◽  
John Q. Wang ◽  
...  
Keyword(s):  
Ion Channels ◽  
Underlying Mechanism ◽  
Cation Channels ◽  
Ischemic Brain Injury ◽  
Mechanical Forces ◽  
Sodium Permeability ◽  
Ischemic Brain ◽  
Acid Sensing Ion Channels ◽  
The Central Nervous System ◽  
Spring Mechanism

Acid-sensing ion channels (ASICs) are mainly proton-gated cation channels that are activated by pH drops and nonproton ligands. They are part of the degenerin/epithelial sodium channel superfamily due to their sodium permeability. Predominantly expressed in the central nervous system, ASICs are involved in synaptic plasticity, learning/memory, and fear conditioning. These channels have also been implicated in multiple disease conditions, including ischemic brain injury, multiple sclerosis, Alzheimer’s disease, and drug addiction. Recent research has illustrated the involvement of ASICs in mechanosensation. Mechanosensation is a form of signal transduction in which mechanical forces are converted into neuronal signals. Specific mechanosensitive functions have been elucidated in functional ASIC1a, ASIC1b, ASIC2a, and ASIC3. The implications of mechanosensation in ASICs indicate their subsequent involvement in functions such as maintaining blood pressure, modulating the gastrointestinal function, and bladder micturition, and contributing to nociception. The underlying mechanism of ASIC mechanosensation is the tether-gate model, which uses a gating-spring mechanism to activate ASIC responses. Further understanding of the mechanism of ASICs will help in treatments for ASIC-related pathologies. Along with the well-known chemosensitive functions of ASICs, emerging evidence has revealed that mechanosensitive functions of ASICs are important for maintaining homeostasis and contribute to various disease conditions.

scholarly journals Acid-Sensing Ion Channels Activated by Evoked Released Protons Modulate Synaptic Transmission at the Mouse Calyx of Held Synapse

2017 ◽  
Vol 37 (10) ◽  
pp. 2589-2599 ◽  
Author(s):  
Carlota González-Inchauspe ◽  
Francisco J. Urbano ◽  
Mariano N. Di Guilmi ◽  
Osvaldo D. Uchitel
Keyword(s):  
Ion Channels ◽  
Synaptic Transmission ◽  
Calyx Of Held ◽  
Acid Sensing Ion Channels

scholarly journals The Tarantula Toxin Psalmotoxin 1 Inhibits Acid-sensing Ion Channel (ASIC) 1a by Increasing Its Apparent H+ Affinity

2005 ◽  
Vol 126 (1) ◽  
pp. 71-79 ◽  
Author(s):  
Xuanmao Chen ◽  
Hubert Kalbacher ◽  
Stefan Gründer
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Therapeutic Intervention ◽  
Mechanical Stimuli ◽  
Apparent Affinity ◽  
Brain Functions ◽  
Acid Sensing Ion Channels ◽  
Higher Brain Functions ◽  
Unique Mechanism

Acid-sensing ion channels (ASICs) are ion channels activated by extracellular protons. They are involved in higher brain functions and perception of pain, taste, and mechanical stimuli. Homomeric ASIC1a is potently inhibited by the tarantula toxin psalmotoxin 1. The mechanism of this inhibition is unknown. Here we show that psalmotoxin 1 inhibits ASIC1a by a unique mechanism: the toxin increases the apparent affinity for H+ of ASIC1a. Since ASIC1a is activated by H+ concentrations that are only slightly larger than the resting H+ concentration, this increase in H+ affinity is sufficient to shift ASIC1a channels into the desensitized state. As activation of ASIC1a has recently been linked to neurodegeneration associated with stroke, our results suggest chronic desensitization of ASIC1a by a slight increase of its H+ affinity as a possible way of therapeutic intervention in stroke.

scholarly journals Transient acidosis while retrieving a fear-related memory enhances its lability

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jianyang Du ◽  
Margaret P Price ◽  
Rebecca J Taugher ◽  
Daniel Grigsby ◽  
Jamison J Ash ◽  
...  
Keyword(s):  
Ion Channels ◽  
Synaptic Transmission ◽  
Pavlovian Conditioning ◽  
Ampa Receptors ◽  
Memory Trace ◽  
Aversive Event ◽  
Synaptic Signaling ◽  
Acid Sensing Ion Channels ◽  
Labile State ◽  
Conditioning Experiments

Attenuating the strength of fearful memories could benefit people disabled by memories of past trauma. Pavlovian conditioning experiments indicate that a retrieval cue can return a conditioned aversive memory to a labile state. However, means to enhance retrieval and render a memory more labile are unknown. We hypothesized that augmenting synaptic signaling during retrieval would increase memory lability. To enhance synaptic transmission, mice inhaled CO2 to induce an acidosis and activate acid sensing ion channels. Transient acidification increased the retrieval-induced lability of an aversive memory. The labile memory could then be weakened by an extinction protocol or strengthened by reconditioning. Coupling CO2 inhalation to retrieval increased activation of amygdala neurons bearing the memory trace and increased the synaptic exchange from Ca2+-impermeable to Ca2+-permeable AMPA receptors. The results suggest that transient acidosis during retrieval renders the memory of an aversive event more labile and suggest a strategy to modify debilitating memories.

scholarly journals Mambalgin-3 potentiates human acid-sensing ion channel 1b under mild to moderate acidosis: Implications as an analgesic lead

2021 ◽  
Vol 118 (8) ◽  
pp. e2021581118
Author(s):  
Ben Cristofori-Armstrong ◽  
Elena Budusan ◽  
Lachlan D. Rash
Keyword(s):  
Nervous System ◽  
Ion Channels ◽  
Ion Channel ◽  
Mechanism Of Action ◽  
Peptide Inhibitors ◽  
Structure Activity ◽  
Pain Pathways ◽  
Acid Sensing Ion Channels ◽  
Human Acid ◽  
Potential Therapeutics

Acid-sensing ion channels (ASICs) are expressed in the nervous system, activated by acidosis, and implicated in pain pathways. Mambalgins are peptide inhibitors of ASIC1 and analgesic in rodents via inhibition of centrally expressed ASIC1a and peripheral ASIC1b. This activity has generated interest in mambalgins as potential therapeutics. However, most mechanism and structure–activity relationship work on mambalgins has focused on ASIC1a, and neglected the peripheral analgesic target ASIC1b. Here, we compare mambalgin potency and mechanism of action at heterologously expressed rat and human ASIC1 variants. Unlike the nanomolar inhibition at ASIC1a and rodent ASIC1b, we find mambalgin-3 only weakly inhibits human ASIC1b and ASIC1b/3 under severe acidosis, but potentiates currents under mild/moderate acidosis. Our data highlight the importance of understanding the activity of potential ASIC-targeting pharmaceuticals at human channels.

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