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TRP channels: a journey towards a molecular understanding of pain

Nature Reviews Neuroscience volume 23, pages 596–610 (2022)Cite this article

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Abstract

The perception of nociceptive signals, which are translated into pain, plays a fundamental role in the survival of organisms. Because pain is linked to a negative sensation, animals learn to avoid noxious signals. These signals are detected by receptors, which include some members of the transient receptor potential (TRP) family of ion channels that act as transducers of exogenous and endogenous noxious cues. These proteins have been in the focus of the field of physiology for several years, and much knowledge of how they regulate the function of the cell types and organs where they are expressed has been acquired. The last decade has been especially exciting because the ‘resolution revolution’ has allowed us to learn the molecular intimacies of TRP channels using cryogenic electron microscopy. These findings, in combination with functional studies, have provided insights into the role played by these channels in the generation and maintenance of pain.

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Fig. 1: Pain and its molecular effectors.
Fig. 2: Electrophilic activation of TRPA1 and Ca2+ priming of TRPM2.
Fig. 3: Activation and sensitization of TRPV1 produces chest pain.
Fig. 4: A biophysical property of TRPV1 that can affect pain.
Fig. 5: Structural rearrangements in heat-activated TRPV1.

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Acknowledgements

This research was funded by the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica of the Dirección General de Asuntos del Personal Académico (IN200720 to T.R. and IN215621 to L.D.I.), the Consejo Nacional de Ciencia y Tecnología (A1-S-8760 to T.R) and the Secretaría de Educación, Ciencia, Tecnología e Innovación del Gobierno de la Ciudad de México (SECTEI/208/2019 to T.R). The authors thank A. Llorente for help in the production of the figures.

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  1. Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, UNAM, Mexico City, Mexico

    Tamara Rosenbaum & Sara L. Morales-Lázaro

  2. Departamento de Fisiología, Facultad de Medicina, UNAM, Mexico City, Mexico

    León D. Islas

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T.R., S.L.M-L. and L.I. researched data for and wrote the article. T.R and L.I made substantial contributions to discussion of the content and reviewed and edited the manuscript before submission.

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Glossary

Pain

An unpleasant sensation that can compromise the quality of life of an individual. It is a widely prevalent condition that, in several ways, remains elusive to diagnosis and treatment.

Polymodal

The ability to respond to different types of stimulus or sensory information, such as touch, heat and chemicals.

Melastatin homology regions

Sequences shared by ion channels of the transient receptor potential melastatin (TRPM) family that are present in their amino termini instead of the ankyrin repeats found in canonical (TRPC) and vanilloid (TRPV) TRP channels.

Electrophilic compounds

Compounds that form covalent bonds with nucleophiles such as cysteine residues by accepting an electron pair.

Allodynia

Pain in response to a stimulus that does not usually produce pain.

Hyperalgesia

Increased sensitivity to a painful stimulus. Both hyperalgesia and analgesia (the inhibition of pain) can be present in some individuals with neuropathic pain.

Hysteretic properties

Ion channel behaviour where reversal of the activating stimulus does not result in a return to the initial state following the same pathway and implies the presence of memory, which is generally associated with irreversible gating steps.

Odontoblasts

Columnar cells localized to the periphery of the dental pulp that form dentine by controlling mineralization processes in teeth.

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Rosenbaum, T., Morales-Lázaro, S.L. & Islas, L.D. TRP channels: a journey towards a molecular understanding of pain. Nat Rev Neurosci 23, 596–610 (2022). https://doi.org/10.1038/s41583-022-00611-7

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