Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms

Abstract

Please cite this article as: Cristofori-Armstrong, B., Rash, L.D., Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms, Neuropharmacology (2017), doi: 10.1016/j.neuropharm.2017.04.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT2 ABSTRACT Acid-sensing ion channels (ASICs) are proton-activated cation channels that are expressed in a variety of neuronal and non-neuronal tissues. As proton-gated channels, they have been implicated in many pathophysiological conditions where pH is perturbed. Venom derived compounds represent the most potent and selective modulators of ASICs described to date, and thus have been invaluable as pharmacological tools to study ASIC structure, function, and biological roles. There are now ten ASIC modulators described from animal venoms, with those from snakes and spiders favouring ASIC1, while the sea anemones preferentially target ASIC3. Some modulators, such as the prototypical ASIC1 modulator PcTx1 have been studied in great detail, while some of the newer members of the club remain largely unstudied. Here we review the current state of knowledge on venom derived ASIC modulators, with a particular focus on their molecular interaction with ASICs, what they have taught us about channel structure, and what they might still reveal about ASIC function and pathophysiological roles.

Inhibition of acid‐sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain

“…Given our reliance on pharmacological tools to study the role of ASICs in nociception, it is of utmost importance to understand the selectivity and mechanisms of action of the pharmacological agents used as fully as possible, in order to ensure meaningful data interpretation. Although the number of pharmacological tools available to study ASICs has increased greatly in the last 10 years, many of them are either non‐selective, not as selective as first thought, or insufficiently characterized (Cristofori‐Armstrong and Rash, ; Rash, ). Two examples of this are APETx2 and the veterinary diarylamidine drug, diminazene aceturate (hereafter, diminazene).…”

Synaptic signals mediated by protons and acid‐sensing ion channels

“…ASICs, also called proton‐gated channels (Waldmann, Champigny, et al, ) play an important role in signal transduction as an exquisite proton sensor in the nervous system (for an extensive review see Cristofori‐Armstrong & Rash, ; Grunder & Pusch, ; Kellenberger & Schild, ; Wemmie, Taugher, & Kreple, ).…”

Toxins as tools: Fingerprinting neuronal pharmacology

“…In mammals, six different ASIC subunits have been described (ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, ASIC4) that combine to form either homo-or hetero-trimers. Toxins that target ASICs have been isolated from the venom of spiders, snakes and sea anemones, and have been pivotal in establishing the role of ASICs in ischemic stroke, neuronal inflammation, and pain [41].…”