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 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 Role of Transient Receptor Potential and Acid-sensing Ion Channels in Peripheral Inflammatory Pain

2010 ◽  
Vol 112 (3) ◽  
pp. 729-741 ◽  
Author(s):  
John P. M. White ◽  
Mario Cibelli ◽  
Antonio Rei Fidalgo ◽  
Cleoper C. Paule ◽  
Faruq Noormohamed ◽  
...  
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Ionotropic Receptors ◽  
Acid Sensing Ion Channels ◽  
Peripheral Pain ◽  
Transient Receptor

Pain originating in inflammation is the most common pathologic pain condition encountered by the anesthesiologist whether in the context of surgery, its aftermath, or in the practice of pain medicine. Inflammatory agents, released as components of the body's response to peripheral tissue damage or disease, are now known to be collectively capable of activating transient receptor potential vanilloid type 1, transient receptor potential vanilloid type 4, transient receptor potential ankyrin type 1, and acid-sensing ion channels, whereas individual agents may activate only certain of these ion channels. These ionotropic receptors serve many physiologic functions-as, indeed, do many of the inflammagens released in the inflammatory process. Here, we introduce the reader to the role of these ionotropic receptors in mediating peripheral pain in response to inflammation.

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 A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channels

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Yangyu Wu ◽  
Zhuyuan Chen ◽  
Cecilia M Canessa
Keyword(s):  
Steady State ◽  
Ion Channels ◽  
Molecular Mechanism ◽  
Sodium Channels ◽  
Xenopus Oocytes ◽  
Acid Sensing Ion Channels ◽  
Electrophysiological Measurements ◽  
Open States

ASICs are proton-gated sodium channels expressed in neurons. Structures of chicken ASIC1 in three conformations have advanced understanding of proton-mediated gating; however, a molecular mechanism describing desensitization from open and pre-open states (steady-state desensitization or SSD) remains elusive. A distinct feature of the desensitized state is an 180o rotation of residues L415 and N416 in the β11- β12 linker that was proposed to mediate desensitization; whether and how it translates into desensitization has not been explored yet. Using electrophysiological measurements of injected Xenopus oocytes, we show that Q276 in β9 strand works with L415 and N416 to mediate both types of desensitization in ASIC1a, ASIC2a and ASIC3. Q276 functions as a valve that enables or restricts rotation of L415 and N416 to keep the linker compressed, its relaxation lengthens openings and leads to sustained currents. At low proton concentrations, the proposed mechanism working in only one of three subunits of the channel is sufficient to induce SSD.

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 Single Channel Properties of Rat Acid–sensitive Ion Channel-1α, -2a, and -3 Expressed in Xenopus Oocytes

2002 ◽  
Vol 120 (4) ◽  
pp. 553-566 ◽  
Author(s):  
Ping Zhang ◽  
Cecilia M. Canessa
Keyword(s):  
Ion Channels ◽  
Xenopus Oocytes ◽  
Single Channel ◽  
Patch Clamp Technique ◽  
Open Probability ◽  
Acid Sensing Ion Channels ◽  
Voltage Dependent ◽  
Subconductance States ◽  
Kinetics Of ◽  
Channel Properties

The mammalian nervous system expresses proton-gated ion channels known as acid-sensing ion channels (ASICs). Depending on their location and specialization some neurons express more than one type of ASIC where they may form homo- or heteromeric channels. Macroscopic characteristics of the ASIC currents have been described, but little is known at the single channel level. Here, we have examined the properties of unitary currents of homomeric rat ASIC1α, ASIC2a, and ASIC3 expressed in Xenopus oocytes with the patch clamp technique. We describe and characterize properties unique to each of these channels that can be used to distinguish the various types of ASIC channels expressed in mammalian neurons. The amplitudes of the unitary currents in symmetrical Na+ are similar for the three types of channels (23–18 pS) and are not voltage dependent. However, ASIC1α exhibits three subconductance states, ASIC2a exhibits only one, and ASIC3 none. The kinetics of the three types of channels are different: ASIC1α and ASIC2a shift between modes of activity, each mode has different open probability and kinetics. In contrast, the kinetics of ASIC3 are uniform throughout the burst of activity. ASIC1α, ASIC2a, and ASIC3 are activated by external protons with apparent pH50 of 5.9, 5.0, and 5.4, respectively. Desensitization in the continual presence of protons is fast and complete in ASIC1α and ASIC3 (2.0 and 4.5 s−1, respectively) but slow and only partial in ASIC2a (0.045 s−1). The response to external Ca2+ also differs: μM concentrations of extracellular Ca2+ are necessary for proton gating of ASIC3 (EC50 = 0.28 μM), whereas ASIC1α and ASIC2a do not require Ca2+. In addition, Ca2+ inhibits ASIC1α (KD = 9.2 ± 2 mM) by several mechanisms: decrease in the amplitude of unitary currents, shortening of the burst of activity, and decrease in the number of activated channels. Contrary to previous reports, our results indicate that the Ca2+ permeability of ASIC1α is very small.

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.

Sign in / Sign up

Export Citation Format

Share Document