Venom toxins in the exploration of molecular, physiological and pathophysiological functions of acid-sensing ion channels

International audienceAcid-sensing ion channels (ASICs) are voltage-independent proton-gated cation channels that are largely expressed in the nervous system as well as in some non-neuronal tissues. In rodents, six different isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4) can associate into homo-or hetero-trimers to form a functional channel. Specific polypeptide toxins targeting ASIC channels have been isolated from the venoms of spider (PcTx1), sea anemone (APETx2) and snakes (MitTx and mambalgins). They exhibit different and sometimes partially overlapping pharmacological profiles and are usually blockers of ASIC channels, except for MitTx, which is a potent activator. This review focuses on the use of these toxins to explore the structure-function relationships, the physiological and the pathophysiological roles of ASIC channels, illustrating at the same time the therapeutic potential of some of these natural compounds

Spadin, a Sortilin-Derived Peptide, Targeting Rodent TREK-1 Channels: A New Concept in the Antidepressant Drug Design

We found that spadin, a natural peptide derived from sortilin, blocks the mouse TREK-1 channel and might be an efficient and fast-acting antidepressant

Acid-Sensing Ion Channels and nociception in the peripheral and central nervous systems

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Activité et expression de l'échangeur Na+/Ca2+ dans les cellules musculaires squelettiques de mammifère en culture primaire

POITIERS-BU Sciences (861942102) / SudocSudocFranceF

ASIC3-dependent spinal cord nociceptive signaling in cutaneous pain induced by lysophosphatidyl-choline

ABSTRACTLysophosphatidyl-choline (LPC), a member of the phospholipid family, has recently emerged as an interesting new player in pain. It has been proposed to mediate pain through Acid-Sensing Ion Channel 3 (ASIC3), a pain-related channel mainly expressed in peripheral sensory neurons. LPC potentiates ASIC3 current evoked by mild acidifications, but can also activate the channel at physiological pH, and its local injection in rodents evokes ASIC3-dependent pain. We combine here in vivo recordings of spinal cord neuron activity with subcutaneous LPC injection to analyze the mechanism of action associated with the LPC-induced, ASIC3-dependent pain in peripheral and spinal cord neurons. We show that a single cutaneous injection of LPC exclusively affects the nociceptive pathway. It evokes an ASIC3-dependent short-term sensitization of nociceptive fibers that drives hyperexcitability of projecting neurons within the dorsal spinal cord without apparent central sensitization.</jats:p

Acid-sensing ion channel 3 in retinal function and survival.

International audiencePURPOSE: Changes in extracellular pH occur in the retina and directly affect retinal activity and phototransduction. The authors analyzed the expression in rodent retina of ASIC3, a sensor of extracellular acidosis, and used ASIC3 knockout mice to explore its role in retinal function and survival. METHODS: The expression and the role of ASIC3 were examined by immunolocalization and by comparing retinas from wild-type and knockout mice at different ages through electroretinography, retinal histology (light and electron microscopy), expression of glial fibrillary acidic protein (GFAP), analysis of cell apoptosis (TUNEL assay), and patch-clamp recordings in primary cultures of retinal ganglion cells (RGCs). RESULTS: ASIC3 is present in the rod inner segment of photoreceptors and in horizontal and some amacrine cells. ASIC3 is also detected in RGCs but does not significantly contribute to ASIC currents recorded in cultured RGCs. At 2 to 3 months, knockout mice experience a 19% enhancement of scotopic electroretinogram a-wave amplitude and a concomitant increase of b-wave amplitude without alteration of retinal structure. Older (8-month-old) knockout mice have 69% and 64% reductions in scotopic a- and b-waves, respectively, and reductions in oscillatory potential amplitudes associated with complete disorganization of the retina and degenerating rod inner segments. GFAP and TUNEL staining performed at 8 and 12 months of age revealed an upregulation of GFAP expression in Müller cells and the presence of apoptotic cells in the inner and outer retina. CONCLUSIONS: Inactivation of ASIC3 enhances visual transduction at 2 to 3 months but induces late-onset rod photoreceptor death, suggesting an important role for ASIC3 in maintaining retinal integrity

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

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

Current perspectives on acid-sensing ion channels: new advances and therapeutic implications

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Single Subcutaneous Injection of Lysophosphatidyl-Choline Evokes ASIC3-Dependent Increases of Spinal Dorsal Horn Neuron Activity

Lysophosphatidyl-choline (LPC), a member of the phospholipid family, is an emerging player in pain. It is known to modulate different pain-related ion channels, including Acid-Sensing Ion Channel 3 (ASIC3), a cationic channel mainly expressed in peripheral sensory neurons. LPC potentiates ASIC3 current evoked by mild acidifications, but can also activate the channel at physiological pH. Very recently, LPC has been associated to chronic pain in patients suffering from fibromyalgia or osteoarthritis. Accordingly, repetitive injections of LPC within mouse muscle or joint generate both persistent pain-like and anxiety-like behaviors in an ASIC3-dependent manner. LPC has also been reported to generate acute pain behaviors when injected intraplantarly in rodents. Here, we explore the mechanism of action of a single cutaneous injection of LPC by studying its effects on spinal dorsal horn neurons. We combine pharmacological, molecular and functional approaches including in vitro patch clamp recordings and in vivo recordings of spinal neuronal activity. We show that a single cutaneous injection of LPC exclusively affects the nociceptive pathway, inducing an ASIC3-dependent sensitization of nociceptive fibers that leads to hyperexcitabilities of both high threshold (HT) and wide dynamic range (WDR) spinal neurons. ASIC3 is involved in LPC-induced increase of WDR neuron’s windup as well as in WDR and HT neuron’s mechanical hypersensitivity, and it participates, together with TRPV1, to HT neuron’s thermal hypersensitivity. The nociceptive input induced by a single LPC cutaneous rather induces short-term sensitization, contrary to previously described injections in muscle and joint. If the effects of peripheral LPC on nociceptive pathways appear to mainly depend on peripheral ASIC3 channels, their consequences on pain may also depend on the tissue injected. Our findings contribute to a better understanding of the nociceptive signaling pathway activated by peripheral LPC via ASIC3 channels, which is an important step regarding the ASIC3-dependent roles of this phospholipid in acute and chronic pain conditions.</jats:p