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 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 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 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 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.

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.

Acid-sensing ion channels

2006 ◽  
pp. S100-S101
Author(s):  
S P H Alexander ◽  
A Mathie ◽  
J A Peters
Keyword(s):  
Ion Channels ◽  
Acid Sensing Ion Channels

Acid Sensing Ion Channels (ASICs) und 5-HT-Rezeptoren bei GERD. Untersuchungen zur Genexpression im pharmakologischen Modell

2015 ◽  
Vol 53 (08) ◽  
Author(s):  
A Shcherbokova ◽  
H Abdel-Aziz ◽  
O Kelber ◽  
K Nieber ◽  
G Ulrich-Merzenich
Keyword(s):  
Ion Channels ◽  
Acid Sensing Ion Channels

Acid-Sensing Ion Channels

2020 ◽  
Author(s):  
Stefan Gründer
Keyword(s):  
Nervous System ◽  
Ion Channels ◽  
Excitatory Synapses ◽  
Detailed Characterization ◽  
High Affinity ◽  
Acid Sensing Ion Channels ◽  
Long Time ◽  
Pathological Pain

Acid-sensing ion channels (ASICs) are proton-gated Na+ channels. Being almost ubiquitously present in neurons of the vertebrate nervous system, their precise function remained obscure for a long time. Various animal toxins that bind to ASICs with high affinity and specificity have been tremendously helpful in uncovering the role of ASICs. We now know that they contribute to synaptic transmission at excitatory synapses as well as to sensing metabolic acidosis and nociception. Moreover, detailed characterization of mouse models uncovered an unanticipated role of ASICs in disorders of the nervous system like stroke, multiple sclerosis, and pathological pain. This review provides an overview on the expression, structure, and pharmacology of ASICs plus a summary of what is known and what is still unknown about their physiological functions and their roles in diseases.

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