Molecules for Nociceptor Force Transduction

Introduction

Pain results from activation of the nociceptive sensory system, which is built upon the primary afferent nociceptor, a type of sensory neuron specialized to detect, code, and relay information about potentially or actually damaging stimuli. Humans lacking properly functioning nociceptors never experience pain and have reduced life expectancy, suffering severe disability.

Nociceptor Function

Nociceptors detect sustained force into ranges that are potentially damaging, and sustained nociceptor activation will always lead to pain. It has been assumed that mechanical force transduced by nociceptors requires mechanically activated ion channels in the nociceptor membrane.

Recent Findings

However, recent data suggests that sensory Schwann cells that wrap the nociceptor ending also participate in force transduction. The aim of this proposal is to identify molecules specifically involved in nociceptor force transduction at this neuroglial site.

Identified Molecules

We have already identified:

1. An ion channel (Tmem87a/ELKIN1)
2. An extracellular tether protein (TENM4)

These molecules are involved in nociceptor force transduction. In addition, STOML3 modulates ELKIN1 function and can sensitize almost all nociceptors to mechanical force.

Research Approach

The identification of a set of molecules involved in force transduction (ELKIN1/TENM4/STOML3) will allow us to design “guilt by association” approaches to identify new players. We will use:

• Ultra-low input spatial proteomics
• BioID
• High throughput electrophysiological screening

to achieve this aim.

Genetic Strategies

We have designed novel genetic strategies to interrogate the function of candidate proteins in nociceptor force transduction, with timescales ranging from weeks to minutes.

Project Impact

This ambitious and challenging project promises to deliver novel molecular targets that can be used to specifically target nociceptor force transduction. Specific targeting of nociceptor force transduction could be a powerful new way to treat multiple pain types poorly served by existing therapies.