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TRPM channels in health and disease

Nature Reviews Nephrology volume 20, pages 175–187 (2024)Cite this article

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Abstract

Different cell channels and transporters tightly regulate cytoplasmic levels and the intraorganelle distribution of cations. Perturbations in these processes lead to human diseases that are frequently associated with kidney impairment. The family of melastatin-related transient receptor potential (TRPM) channels, which has eight members in mammals (TRPM1–TRPM8), includes ion channels that are highly permeable to divalent cations, such as Ca2+, Mg2+ and Zn2+ (TRPM1, TRPM3, TRPM6 and TRPM7), non-selective cation channels (TRPM2 and TRPM8) and monovalent cation-selective channels (TRPM4 and TRPM5). Three family members contain an enzymatic protein moiety: TRPM6 and TRPM7 are fused to α-kinase domains, whereas TRPM2 is linked to an ADP-ribose-binding NUDT9 homology domain. TRPM channels also function as crucial cellular sensors involved in many physiological processes, including mineral homeostasis, blood pressure, cardiac rhythm and immunity, as well as photoreception, taste reception and thermoreception. TRPM channels are abundantly expressed in the kidney. Mutations in TRPM genes cause several inherited human diseases, and preclinical studies in animal models of human disease have highlighted TRPM channels as promising new therapeutic targets. Here, we provide an overview of this rapidly evolving research area and delineate the emerging role of TRPM channels in kidney pathophysiology.

Key points

  • Melastatin-like transient receptor potential (TRPM) channels are multifunctional cation channels with diverse biophysical and physiological characteristics. Eight family members have been defined (TRPM1–TRPM8).

  • TRPM1 and TRPM3 are channels permeable to Ca2+ and Zn2+ regulated by neuroactive steroids that have crucial roles in ON-bipolar neurons of the retina, dorsal root ganglia neurons and other cells.

  • TRPM6 and TRPM7 are bifunctional kinase-coupled channels that control cellular and body homeostasis of Zn2+, Mg2+ and Ca2+.

  • TRPM4 and TRPM5 are Ca2+-activated monovalent cation channels that influence the excitability of neurons and cardiomyocytes, and control the chemosensory activity of taste receptor cells and tuft cells.

  • TRPM2 and TRPM8 are non-selective cation channels. TRPM2 mediates ADP-ribose and reactive oxygen species signalling in neurons, immunocytes and kidney epithelial cells, whereas TRPM8 is a cold-sensing channel that regulates organismal thermal responses.

  • Multiple TRPM channel types are expressed in the kidney, especially TRPM6 and TRPM7. Their physiological relevance awaits clarification, but they might have a role in renal cation homeostasis.

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Fig. 1: The TRPM channel family.
Fig. 2: Functional characteristics of TRPM1–TRPM8 channels, and implications in inherited human diseases.
Fig. 3: The roles of TRPM6 and TRPM7 in the epithelial transport of divalent cations in the kidney and intestine.
Fig. 4: TRPM3, TRPM5 and TRPM8 in urethral reflexes.

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Acknowledgements

V.C., M.K. and T.G. were supported by the Deutsche Forschungsgemeinschaft (DFG), TRR 152 (project ID 239283807, DFG). T.G. was supported by Research Training Group 2338 (DFG). M.K. was supported by SFB1453 (project ID 431984000, DFG) and Germany’s Excellence Strategy (project ID 390939984, CIBSS EXC-2189). R.M.T. was supported by The Canada Research Chair Program (Canadian Institutes of Health Research) and the Dr Phil Gold Chair in Medicine (McGill University, Montreal).

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  1. These authors jointly supervised this work: Vladimir Chubanov, Thomas Gudermann.

Authors and Affiliations

  1. Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany

    Vladimir Chubanov & Thomas Gudermann

  2. Renal Division, Department of Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Michael Köttgen

  3. CIBSS - Centre for Integrative Biological Signalling Studies, Freiburg, Germany

    Michael Köttgen

  4. Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec, Canada

    Rhian M. Touyz

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Glossary

ON-bipolar neurons

Retinal metabotropic neurons with two processes, which transfer information from the photoreceptor cells (rods and cones) to ganglion cells.

ORAI channels

Pore-forming membrane proteins that function as store-operated Ca2+ entry (SOCE) channels, which are also termed Ca2+ release-activated calcium (CRAC) channels.

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Chubanov, V., Köttgen, M., Touyz, R.M. et al. TRPM channels in health and disease. Nat Rev Nephrol 20, 175–187 (2024). https://doi.org/10.1038/s41581-023-00777-y

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