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

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.

Download Full-text

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

eLife ◽

10.7554/elife.22564 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 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.

Download Full-text

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

10.1101/2021.06.21.449215 ◽

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.

Download Full-text

Acid-sensing ion channels

British Journal of Pharmacology ◽

10.1038/sj.bjp.0706605 ◽

2006 ◽

pp. S100-S101

Author(s):

S P H Alexander ◽

A Mathie ◽

J A Peters

Keyword(s):

Ion Channels ◽

Acid Sensing Ion Channels

Download Full-text

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

Zeitschrift für Gastroenterologie ◽

10.1055/s-0035-1559036 ◽

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

Download Full-text

Research Strategies for Pain in Lumbar Radiculopathy Focusing on Acid-Sensing Ion Channels and Their Toxins

Current Topics in Medicinal Chemistry ◽

10.2174/1568026615666150217112652 ◽

2015 ◽

Vol 15 (7) ◽

pp. 617-630 ◽

Cited By ~ 3

Author(s):

Jiann-Her Lin ◽

Yung-Hsiao Chiang ◽

Chih-Cheng Chen

Keyword(s):

Ion Channels ◽

Lumbar Radiculopathy ◽

Research Strategies ◽

Acid Sensing Ion Channels

Download Full-text

Acid-Sensing Ion Channels

The Oxford Handbook of Neuronal Ion Channels ◽

10.1093/oxfordhb/9780190669164.013.12 ◽

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.

Download Full-text