The TRPM8 Protein Is a Testosterone Receptor

Asuthkar, Swapna; Demirkhanyan, Lusine; Sun, Xinwei; Elustondo, Pia A.; Krishnan, Vivek; Baskaran, Padmamalini; Velpula, Kiran Kumar; Thyagarajan, Baskaran; Pavlov, Evgeny; Zakharian, Eleonora

doi:10.1074/jbc.m114.610873

Cited by 103 publications

(65 citation statements)

References 37 publications

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“…This regulatory role of TRPM8 is disrupted during prostate cancer development caused by the intense protein degradation that might lead to diminished rates of rapid Ca 2+ intake, and simultaneously, uncoupled testosterone levels in the absence of its high-affinity receptor [5]. This proposition for the role of TRPM8 in prostate cancer is depicted in the scheme, presented in Figure 8.…”

Section: Resultsmentioning

confidence: 99%

High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer

et al. 2016

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The Ca2+-permeable ion channel TRPM8 is a hallmark of the prostate epithelium. We recently discovered that TRPM8 is an ionotropic testosterone receptor. This finding suggested that testosterone-induced TRPM8 activity regulates Ca2+ homeostasis in the prostate epithelium. Since androgens are significantly implicated in prostate cancer development, the role of the novel testosterone receptor TRPM8 in cancer was assessed in our study. Although TRPM8 mRNA levels increase at the early prostate cancer stages, we found that it is not proportionally translated into TRPM8 protein levels. High-throughput proteome analysis revealed that TRPM8 degradation is enhanced in human prostate cancer cells. This degradation is executed via a dual degradation mechanism with the involvement of both lysosomal and proteasomal proteolytic pathways. The evaluation of the TRPM8 expression pattern in prostate cancer patients further confirmed the incidence of TRPM8 removal from the plasma membrane and its internalization pattern coincided with the severity of the tumor. Together, our results indicate that enhanced TRPM8 hydrolysis in prostate cancer could present an adaptation mechanism, sustained via bypassing testosterone-induced rapid Ca2+ uptake through TRPM8, thus, diminishing the rates of apoptosis. In this light, recovery of TRPM8 may pose a novel therapeutic strategy for an anti-tumor defense mechanism.

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Section: Resultsmentioning

confidence: 99%

High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer

et al. 2016

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“…Besides being stimulated by cooling and menthol, 4, 5, 98 the TRPM8 channel is regulated by second messengers. PIP2 in particular, is an allosteric enhancer of TRPM8 at the cytoplasmic surface of the cell membrane.…”

Section: Discussionmentioning

confidence: 99%

Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia

Gong

Jasmin

2017

The Journal of Pain

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It is not uncommon for patients chronically treated with opioids to exhibit opioid induced hyperalgesia (OIH), and this has been widely reported both clinically and experimentally. The molecular substrate for this hyperalgesia is multifaceted, and associated with a complex neural reorganization even in the periphery. For instance, we have recently shown that chronic morphine-induced heat hyperalgesia is associated with an increased expression of GluN2B containing N-methyl-D-aspartate (NMDA) receptors, as well as of the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1, in small diameter primary sensory neurons only. Cold allodynia is also a common complaint of patients chronically treated with opioids, yet its molecular mechanisms remain to be understood. Here we present evidence that the cold sensor TRPM8 channel is involved in OIH. After 7 days of morphine administration, we observed an upregulation of TRPM8 channels both by patch clamp recording on sensory neurons and western blot on dorsal root ganglia (DRGs). The selective TRPM8 antagonist RQ-00203078 blocked cold hyperalgesia in morphine treated rats. Also, TRPM8 knockout mice (KO) failed to develop cold hyperalgesia after chronic administration of morphine. Our results demonstrate that chronic morphine upregulates TRPM8 channels, which is in contrast with the previous finding that acute morphine triggers TRPM8 internalization. Perspective Patients receiving chronic opioid are sensitive to cold. We now show in mice and rats that sustained morphine administration induces cold hyperalgesia and an up-regulation of TRPM8. Knockout or selectively blocking TRPM8 reduces morphine induced cold hyperalgesia suggesting TRPM8 is regulated by opioids.

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“…Another, recently identified TRPM8 activator is testosterone [211,212]. Androgen-dependent upregulation of TRPM8 gene expression has long been recognized in androgen-dependent prostate tumors [213].…”

Section: Contributions Of Trp Channels To Skin Biology and Pathophmentioning

confidence: 99%

TRP Channels in Skin Biology and Pathophysiology

Caterina¹,

Pang²

2016

Pharmaceuticals

128

122

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Ion channels of the Transient Receptor Potential (TRP) family mediate the influx of monovalent and/or divalent cations into cells in response to a host of chemical or physical stimuli. In the skin, TRP channels are expressed in many cell types, including keratinocytes, sensory neurons, melanocytes, and immune/inflammatory cells. Within these diverse cell types, TRP channels participate in physiological processes ranging from sensation to skin homeostasis. In addition, there is a growing body of evidence implicating abnormal TRP channel function, as a product of excessive or deficient channel activity, in pathological skin conditions such as chronic pain and itch, dermatitis, vitiligo, alopecia, wound healing, skin carcinogenesis, and skin barrier compromise. These diverse functions, coupled with the fact that many TRP channels possess pharmacologically accessible sites, make this family of proteins appealing therapeutic targets for skin disorders.

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The TRPM8 Protein Is a Testosterone Receptor

Cited by 103 publications

References 37 publications

High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer

High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer

Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia

TRP Channels in Skin Biology and Pathophysiology

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