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Roles of Intramolecular Interactions in the Regulation of TRP Channels

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Reviews of Physiology, Biochemistry and Pharmacology

Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 186))

Abstract

The transient receptor potential (TRP) channels, classified into six (-A, -V, -P, -C, -M, -ML, -N and -Y) subfamilies, are important membrane sensors and mediators of diverse stimuli including pH, light, mechano-force, temperature, pain, taste, and smell. The mammalian TRP superfamily of 28 members share similar membrane topology with six membrane-spanning helices (S1–S6) and cytosolic N-/C-terminus. Abnormal function or expression of TRP channels is associated with cancer, skeletal dysplasia, immunodeficiency, and cardiac, renal, and neuronal diseases. The majority of TRP members share common functional regulators such as phospholipid PIP2, 2-aminoethoxydiphenyl borate (2-APB), and cannabinoid, while other ligands are more specific, such as allyl isothiocyanate (TRPA1), vanilloids (TRPV1), menthol (TRPM8), ADP-ribose (TRPM2), and ML-SA1 (TRPML1). The mechanisms underlying the gating and regulation of TRP channels remain largely unclear. Recent advances in cryogenic electron microscopy provided structural insights into 19 different TRP channels which all revealed close proximity of the C-terminus with the N-terminus and intracellular S4–S5 linker. Further studies found that some highly conserved residues in these regions of TRPV, -P, -C and -M members mediate functionally critical intramolecular interactions (i.e., within one subunit) between these regions. This review provides an overview on (1) intramolecular interactions in TRP channels and their effect on channel function; (2) functional roles of interplays between PIP2 (and other ligands) and TRP intramolecular interactions; and (3) relevance of the ligand-induced modulation of intramolecular interaction to diseases.

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Abbreviations

2-APB:

2-Aminoethoxydiphenyl borate

ARDs:

Ankyrin repeat domains

BTDM:

(2-(Benzo[d][1,3]dioxol-5-ylamino)thiazol-4-yl)((3 S,5 R)-3,5-dimethylpiperidin-1-yl)methanone

CBD:

Cannabinoid

Cryo-EM:

Cryogenic electron microscopy

ER:

Endoplasmic reticulum

HEK:

Human embryonic kidney

HTH:

Helix-turn-helix

MHRs:

TRPM homology regions

ML-SA1:

Mucolipin synthetic agonist 1

PIP2:

Phosphatidylinositol 4,5-bisphosphate

RTx:

Resiniferatoxin

TRP:

Transient receptor potential

VSLD:

Voltage-sensing like domain

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Acknowledgements

This work was supported by the Natural Sciences and Engineering Research Council of Canada and Kidney Foundation of Canada (to X.Z.C.). R.C. was a recipient of the Alberta Innovates Graduate Student Scholarship and the NSERC International Research Training Group Studentship.

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Authors and Affiliations

  1. Program in Cell Biology, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, ON, Canada

    Ruiqi Cai

  2. Department of Physiology, Membrane Protein Disease Research Group, University of Alberta, Edmonton, AB, Canada

    Ruiqi Cai & Xing-Zhen Chen

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  1. Ruiqi Cai
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  2. Xing-Zhen Chen
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Correspondence to Xing-Zhen Chen .

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  1. Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Stine Helene Falsig Pedersen

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Cai, R., Chen, XZ. (2022). Roles of Intramolecular Interactions in the Regulation of TRP Channels. In: Pedersen, S.H.F. (eds) Reviews of Physiology, Biochemistry and Pharmacology. Reviews of Physiology, Biochemistry and Pharmacology, vol 186. Springer, Cham. https://doi.org/10.1007/112_2022_74

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