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Structure of the cold- and menthol-sensing ion channel TRPM8.

ABSTRACT: Transient receptor potential melastatin (TRPM) cation channels are polymodal sensors that are involved in a variety of physiological processes. Within the TRPM family, member 8 (TRPM8) is the primary cold and menthol sensor in humans. We determined the cryo-electron microscopy structure of the full-length TRPM8 from the collared flycatcher at an overall resolution of ~4.1 ångstroms. Our TRPM8 structure reveals a three-layered architecture. The amino-terminal domain with a fold distinct among known TRP structures, together with the carboxyl-terminal region, forms a large two-layered cytosolic ring that extensively interacts with the transmembrane channel layer. The structure suggests that the menthol-binding site is located within the voltage-sensor-like domain and thus provides a structural glimpse of the design principle of the molecular transducer for cold and menthol sensation.

SUBMITTER: Yin Y

PROVIDER: S-EPMC5810135 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Structure of the cold- and menthol-sensing ion channel TRPM8.

Yin Ying Y Wu Mengyu M Zubcevic Lejla L Borschel William F WF Lander Gabriel C GC Lee Seok-Yong SY

Science (New York, N.Y.) 20171207 6372

Transient receptor potential melastatin (TRPM) cation channels are polymodal sensors that are involved in a variety of physiological processes. Within the TRPM family, member 8 (TRPM8) is the primary cold and menthol sensor in humans. We determined the cryo-electron microscopy structure of the full-length TRPM8 from the collared flycatcher at an overall resolution of ~4.1 ångstroms. Our TRPM8 structure reveals a three-layered architecture. The amino-terminal domain with a fold distinct among kno ...[more]

PMID: 29217583

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Project description:Highlights • Tunica dartos smooth muscle (TDSM), which is responsible for scrotal thermoregulation, responds to cooling by enhancement of basal tension, and increase of the amplitude and duration of synaptically-evoked contractions.• TDSM cold-induced tension, but not synaptically-evoked contractions are sensitive to the blockers of TRPM8 cold/menthol receptor.• TRPM8 is localized to the TDSM cells' endoplasmic reticulum and its activation by cold causes intracellular calcium mobilization.• Chemical castration of male rats consequent to pharmacological blockade of androgen receptors eliminates the effects of cold on TDSM tension, but not on synaptically-evoked contractions, and abolishes TRPM8 protein expression.• TRPM8 is an important determinant of cold-dependent contractility of the tunica dartos muscle and scrotal thermoregulation which is crucial for maintaining normal spermatogenesis and male fertility. Tunica dartos smooth muscle (TDSM) lies beneath the scrotal skin, and its contraction leads to scrotum wrinkling upon cooling. However, neither the nature of TDSM cold-sensitivity nor the underlying molecular sensors are well understood. Here we have investigated the role of cold/menthol-sensitive TRPM8 channel in TDSM temperature-dependent contractility. The contraction of isolated male rat TDSM strips was studied by tensiometry. TRPM8 expression was assayed by RT-PCR and fluorescence immunochemistry. Isolated TDSM strips responded to cooling from 33 °C to 20 °C by enhancement of basal tension, and increase of the amplitude and duration of electric field stimulated (EFS) contractions. The effects of cold on basal tension, but not on EFS-contractions, could be 80% inhibited by TRPM8 blockers, capsazepine and BCTC [N-(4‑tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide], and could be partially mimicked by menthol. RT-PCR and immunolabeling showed TRPM8 mRNA and protein expression in TDSM cells with protein labelling being predominantly localized to intracellular compartments. Chemical castration of male rats consequent to the treatment with androgen receptor blocker, flutamide, led to the abrogation of cold effects on TDSM basal tension, but not on EFS-contractions, and to the disappearance of TRPM8 protein expression. We conclude that TRPM8 is involved in the maintenance of basal cold-induced TDSM tonus, but not in sympathetic nerve-mediated contractility, by acting as endoplasmic reticulum Ca2+ release channel whose expression in TDSM cells requires the presence of a functional androgen receptor. Thus, TRPM8 plays a crucial role in scrotal thermoregulation which is important for maintaining normal spermatogenesis and male fertility.

Dataset Information

Structure of the cold- and menthol-sensing ion channel TRPM8.

Publications

Structure of the cold- and menthol-sensing ion channel TRPM8.

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