Acid-Sensing Ion Channel 2: Function and Modulation

Sivils, Andy; Yang, Felix; Wang, John Q.; Chu, Xiang‐Ping

doi:10.3390/membranes12020113

Cited by 10 publications

(11 citation statements)

References 144 publications

(345 reference statements)

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“…Furthermore, genetic studies in humans of a closely related gene ASIC1a have previously demonstrated a link between variants, panic disorder (68), and amygdala volume (69). Although ASIC2 is less well studied or lacked adequate power (70) compared to ASIC1a, there is evidence suggesting that ASIC2 works in concert and regulates neuroplasticity in the brain (71, 72). ASICs are considered potential drug targets in various somatic and psychiatric conditions (64, 72, 73).…”

Section: Discussionmentioning

confidence: 99%

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Identification of Novel Genomic Loci for Anxiety and Extensive Genetic Overlap with Psychiatric Disorders

Tesfaye,

Jaholkowski,

Shadrin

et al. 2023

Preprint

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BackgroundAnxiety disorders are prevalent and anxiety symptoms often co-occur with psychiatric disorders. Here, we aimed to identify genomic risk loci associated with anxiety, characterize its genetic architecture, and genetic overlap with psychiatric disorders.MethodsWe used the largest available GWAS of anxiety (GAD-2 score), schizophrenia, bipolar disorder, major depression, and attention deficit hyperactivity disorder (ADHD). We employed MiXeR and LAVA to characterize the genetic architecture and genetic overlap between the phenotypes. Additionally, conditional and conjunctional false discovery rate analyses were performed to boost the identification of genomic loci associated with anxiety and those shared with psychiatric disorders. Gene annotation and gene set analyses were carried out using OpenTargets and FUMA, respectively.ResultsAnxiety was polygenic with 8.4k estimated genetic risk variants and overlapped extensively with psychiatric disorders (4.1-7.8k variants). Both MiXeR and LAVA revealed predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 154 anxiety loci (139 novel) by conditioning on the psychiatric disorders. We identified loci shared between anxiety and major depression (n= 66), bipolar disorder (n= 19), schizophrenia (n= 51), and ADHD (n= 37). Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways and differential tissue expression in more diverse tissues than those annotated to the shared loci.ConclusionsAnxiety is a highly polygenic phenotype with extensive genetic overlap with psychiatric disorders. These genetic overlaps enabled the identification of novel loci for anxiety and shared loci with psychiatric disorders. The shared genetic architecture may underlie the comorbidity of anxiety, and the identified genetic loci implicate molecular pathways that could become potential drug targets.

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Section: Discussionmentioning

confidence: 99%

“…Although ASIC2 is less well studied or lacked adequate power (70) compared to ASIC1a, there is evidence suggesting that ASIC2 works in concert and regulates neuroplasticity in the brain (71, 72). ASICs are considered potential drug targets in various somatic and psychiatric conditions (64, 72, 73).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Genomic Loci for Anxiety and Extensive Genetic Overlap with Psychiatric Disorders

Tesfaye,

Jaholkowski,

Shadrin

et al. 2023

Preprint

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“…The ASIC2b and ASIC4 subunits do not form functional proton-gated channels by themselves, but ASIC2b can associate with other ASIC subunits to confer new properties and regulations to heterotrimeric channels [ 13 , 23 , 24 ]. ASIC currents are generally transient even if the acidification is maintained, but a sustained phase is associated with expression of ASIC3 or with the presence of the ASIC2b subunit in heterotrimers ( Figure 2 ).…”

Section: Molecular and Functional Properties Of Asicsmentioning

confidence: 99%

Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects

Verkest

Salinas

Diochot

et al. 2022

Toxins

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Acid-sensing ion channels (ASICs) are voltage-independent H+-gated cation channels largely expressed in the nervous system of rodents and humans. At least six isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4) associate into homotrimers or heterotrimers to form functional channels with highly pH-dependent gating properties. This review provides an update on the pharmacological profiles of animal peptide toxins targeting ASICs, including PcTx1 from tarantula and related spider toxins, APETx2 and APETx-like peptides from sea anemone, and mambalgin from snake, as well as the dimeric protein snake toxin MitTx that have all been instrumental to understanding the structure and the pH-dependent gating of rodent and human cloned ASICs and to study the physiological and pathological roles of native ASICs in vitro and in vivo. ASICs are expressed all along the pain pathways and the pharmacological data clearly support a role for these channels in pain. ASIC-targeting peptide toxins interfere with ASIC gating by complex and pH-dependent mechanisms sometimes leading to opposite effects. However, these dual pH-dependent effects of ASIC-inhibiting toxins (PcTx1, mambalgin and APETx2) are fully compatible with, and even support, their analgesic effects in vivo, both in the central and the peripheral nervous system, as well as potential effects in humans.

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“…As outlined in the previous section, ASICs are widely expressed in the mammalian nervous system in general and the brain in particular. The list of established functions of this receptor family is already long and is rapidly increasing (for instance, reviewed in [ 102 , 103 ]). ASICs are involved in many important physiological functions, as well as contributing to a variety of pathologies.…”

Section: Asics In Brain Pathologymentioning

confidence: 99%

Triggering of Major Brain Disorders by Protons and ATP: The Role of ASICs and P2X Receptors

et al. 2022

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Adenosine triphosphate (ATP) is well-known as a universal source of energy in living cells. Less known is that this molecule has a variety of important signaling functions: it activates a variety of specific metabotropic (P2Y) and ionotropic (P2X) receptors in neuronal and non-neuronal cell membranes. So, a wide variety of signaling functions well fits the ubiquitous presence of ATP in the tissues. Even more ubiquitous are protons. Apart from the unspecific interaction of protons with any protein, many physiological processes are affected by protons acting on specific ionotropic receptors—acid-sensing ion channels (ASICs). Both protons (acidification) and ATP are locally elevated in various pathological states. Using these fundamentally important molecules as agonists, ASICs and P2X receptors signal a variety of major brain pathologies. Here we briefly outline the physiological roles of ASICs and P2X receptors, focusing on the brain pathologies involving these receptors.

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Acid-Sensing Ion Channel 2: Function and Modulation

Cited by 10 publications

References 144 publications

Identification of Novel Genomic Loci for Anxiety and Extensive Genetic Overlap with Psychiatric Disorders

Identification of Novel Genomic Loci for Anxiety and Extensive Genetic Overlap with Psychiatric Disorders

Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects

Triggering of Major Brain Disorders by Protons and ATP: The Role of ASICs and P2X Receptors

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