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UniProt release 2019_06

Published July 3, 2019


The three-peptide itch

Just like pain, itch is a signal provided to our brain that something is wrong, or potentially dangerous. Contrary to pain, where our reflex leads to withdraw from danger, an itch leads to scratching, in order to remove the irritating, potentially toxic agent, be it an insect or a chemical. Although itching in response to environmental cues is crucial for survival, chronic itch can be debilitating and severely impact the well-being of affected persons. It is known that itch is relayed from the skin, via the dorsal root ganglion neurons, to the second order neurons in the spinal cord that project to the brain. Several Mas-related G-protein coupled receptors (MRGPRs) have been identified as the primary targets of itch signals, and many of them, including MRGPRX1 (also called MrgprC11 in rodents) and Mrgpra3, are activated by the anti-malarial drug chloroquine.

However, the molecular and neural mechanisms of itch are not well elucidated, which is why the discovery of new tools to identify itch receptors and develop new drugs is extremely valuable. In this context, conotoxins have proven to be a gold mine. Conotoxins are produced by cone snails as part of an envenomation survival strategy for feeding and defense. They are short peptides (usually 10 to 30 amino acid residues), typically with one or more disulfide bonds. Many of them modulate the activity of ion channels and receptors with very high affinity and specificity. They can be highly selective between closely related receptor subtypes, therefore they could meet specific therapeutic needs with a reduced likelihood of side effects due to off-target drug effects.

In mice, the injection of Conus textile venom, but not that of C. geographus induced a scratching reflex, which was accompanied by the activation of 89% of sensory neurons that were also sensitive to chloroquine. Two peptides, CNF-Tx1 and CNF-Tx2, were isolated from C. textile venom gland and tested in vitro for their activity on MRGPRX1. In parallel, the same activity was measured for two additional peptides, CNF-Sr1 and CNF-Sr2, previously identified in C. spurious and one, CNF-Vc1, from C. victoriae. Three of these peptides were able to activate MRGPRX1: CNF-Tx2 activated the human, but not the mouse ortholog, CNF-Sr1 activates only the mouse, but not the human ortholog, and CNF-Vc1 activated both. CNF-Tx2 and CNF-Vc1 were then tested in a humanized mouse transgenic line, which has a knockout of the entire endogenous MRGPR cluster and expresses human MRGPRX1 in primary sensory neurons. In this setting, both peptides elicited a scratching reflex, further confirming that CNF-Tx2 and CNF-Vc1 act via the itch receptor MRGPRX1. Compared with the well-established MrgprX1 agonist chloroquine, CNF-Tx2 and CNF-Vc1 were 600 times and 200 times more potent, respectively.

The 5 conopeptides have been updated in UniProtKB/Swiss-Prot and are publicly available.

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