Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Although the mechanisms for some of these functions have been identified, the molecules essential to the sense of pain have remained elusive. Here we report identification of TACAN (Tmem120A), an ion channel involved in sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. Finally, a nociceptor-specific inducible knockout of TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to painful mechanical stimuli but not to thermal or touch stimuli. We propose that TACAN is an ion channel that contributes to sensing mechanical pain.

These results suggest that MSICs are sensitized during OA and directly contribute to mechanical allodynia. They therefore represent potential therapeutic targets in the treatment of OA pain.

The lionfish (Pterois volitans) is a venomous invasive species found in the Caribbean and Northwestern Atlantic. It poses a growing health problem because of the increase in frequency of painful stings, for which no treatment or antidote exists, and the long-term disability caused by the pain. Understanding the venom's algogenic properties can help identify better treatment for these envenomations. In this study, we provide the first characterization of the pain and inflammation caused by lionfish venom and examine the mechanisms through which it causes pain using a combination of in vivo and in vitro approaches including behavioral, physiological, calcium imaging, and electrophysiological testing. Intraplantar injections of the venom produce a significant increase in pain behavior, as well as a marked increase in mechanical sensitivity for up to 24 hours after injection. The algogenic substance(s) are heat-labile peptides that cause neurogenic inflammation at the site of injection and induction of Fos and microglia activation in the superficial layers of the dorsal horn. Finally, calcium imaging and electrophysiology experiments show that the venom acts predominantly on nonpeptidergic, TRPV1-negative, nociceptors, a subset of neurons implicated in sensing mechanical pain. These data provide the first characterization of the pain and inflammation caused by lionfish venom, as well as the first insight into its possible cellular mechanism of action.

Nature’s library of venoms is a vast and untapped resource that has the potential of becoming the source of a wide variety of new drugs and therapeutics. The discovery of these valuable molecules, hidden in diverse collections of different venoms, requires highly specific genetic and proteomic sequencing techniques. These have been used to sequence a variety of venom glands from species ranging from snakes to scorpions, and some marine species. In addition to identifying toxin sequences, these techniques have paved the way for identifying various novel evolutionary links between species that were previously thought to be unrelated. Furthermore, proteomics-based techniques have allowed researchers to discover how specific toxins have evolved within related species, and in the context of environmental pressures. These techniques allow groups to discover novel proteins, identify mutations of interest, and discover new ways to modify toxins for biomimetic purposes and for the development of new therapeutics.

Supplemental Digital Content is Available in the Text. Patients diagnosed with Christianson syndrome have intellectual disability, epilepsy, ataxia, and mutism, as well as hyposensitivity to pain. In this study, we use a mouse model of Christianson syndrome to demonstrate that this pain hyposensitivity is due in part to a decrease in excitability of nociceptors.