Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Mutations in ion channels contribute to neurological disorders, but determining the basis of their role in pathophysiology is often unclear. In humans, 2 mutations have been found to produce a dominant negative for TRESK, a two-pore-domain K+ channel implicated in migraine: TRESK-MT, a 2 bp frameshift mutation (F139WfsX24) and TRESK-C110R, a missense mutation. Despite the fact that both mutants strongly inhibit TRESK, only TRESK-MT leads to an increase in sensory neuron excitability and is associated with a migraine phenotype. Here, we identify a new mechanism, termed frameshift mutation induced Alternative Translation Initiation (fsATI) that may explain why TRESK-MT but not TRESK-C110R is associated with migraine disorder. fsATI leads, from the same TRESK-MT mRNA, to two proteins: TRESK-MT1 and TRESK-MT2. We show that by co-assembling with and inhibiting TREK1 and TREK2, another subfamily of K2P channels, overexpression of TRESK-MT2 increases trigeminal sensory neuron excitability, a key component of migraine induction, leading to a migraine-like phenotype. This finding identifies TREK as a potential molecular target in migraine pathophysiology and resolves the contradictory lack of effect of TRESK-C110R which targets only TRESK and not TREK. Finally, taking into account the potential for fsATI allowed us to identify a new migraine-related TRESK mutant, Y121LfsX44, which also leads to the production of two TRESK fragments, indicating that this mechanism may be widespread. Together, our results suggest that genetic analysis of disease-related mutations should consider fsATI as a distinct class of mutations

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

TREK channel activation suppresses migraine pain phenotype

International audienceActivation and sensitization of trigeminal ganglia (TG) sensory neurons, leading to the release of pro-inflammatory peptides such as calcitonin gene-related peptide (CGRP), are likely a key component in migraine-related headache induction. Reducing TG neuron excitability represents therefore an attractive alternative strategy to relieve migraine pain. Here by using pharmacology and genetic invalidation ex vivo and in vivo, we demonstrate that activating TREK1 and TREK2 two-pore-domain potassium (K2P) channels inhibits TG neuronal firing sufficiently to fully reverse the migraine-like phenotype induced by NO-donors in rodents. Finally, targeting TREK is as efficient as treatment with CGRP antagonists, which represents one of the most effective migraine therapies. Altogether, our results demonstrate that inhibiting TG excitability by pharmacological activation of TREK channels should be considered as an alternative to the current migraine treatment

Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

International audienceIt is often unclear why some genetic mutations to a given gene contribute to neurological disorders and others do not. For instance, two mutations have previously been found to produce a dominant negative for TRESK, a two-pore-domain K+ channel implicated in migraine: TRESK-MT, a 2-bp frameshift mutation, and TRESK-C110R. Both mutants inhibit TRESK, but only TRESK-MT increases sensory neuron excitability and is linked to migraine. Here, we identify a new mechanism, termed frameshift mutation-induced alternative translation initiation (fsATI), that may explain why only TRESK-MT is associated with migraine. fsATI leads to the production of a second protein fragment, TRESK-MT2, which co-assembles with and inhibits TREK1 and TREK2, two other two-pore-domain K+ channels, to increase trigeminal sensory neuron excitability, leading to a migraine-like phenotype in rodents. These findings identify TREK1 and TREK2 as potential molecular targets in migraine and suggest that fsATI should be considered as a distinct class of mutations