Sea anemone Cys‐ladder peptide Ms13‐1 induces a pain response as a positive modulator of acid‐sensing ion channel 1a

Acid-sensing ion channel 1a (ASIC1a) is involved in processes associated with fear, learning, and neurodegeneration within the central nervous system. However, ASIC1a is also abundant in the peripheral nervous system, where its role is still poorly understood, largely due to the lack of selective ligands. In this study, we present the discovery of the first selective positive allosteric modulator for ASIC1a, isolated from the sea anemone Metridium senile. The active compound, a peptide named Ms13-1, features a novel type of fold named 'Cys-ladder'. Ms13-1 exhibits high affinity and selectivity for ASIC1a, enhancing channel activation in response to a broad range of acidic stimuli (pH 6.9-5.5) without altering the proton affinity for the channel. Moreover, injection of Ms13-1 into the hind paw of mice provokes robust and long-lasting pain-related behavior, which is significantly attenuated by a selective ASIC1 antagonist. The discovery of this novel selective positive allosteric modulator opens up new perspectives to investigate the role of ASIC1a in various physiological processes.