Regulation of TRPM8 channel activity

Yudin, Yevgen; Rohács, Tibor

doi:10.1016/j.mce.2011.10.023

Cited by 70 publications

(57 citation statements)

References 89 publications

(165 reference statements)

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“…The regulation of TRPM8 channels, a calcium-dependent process, has been suggested to play a role in the rapid adaptation to prolonged cooling stimulation and involves several factors (Abe et al 2006;Daniels et al 2009;Sarria and Gu 2010;Sarria et al 2011;Thut et al 2003). TRPM8 activity is increased by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and reduced by phospholipase C-mediated hydrolysis of PIP 2 (Daniels et al 2009;Rohacs et al 2005;Yudin et al 2011;Yudin and Rohacs 2012). Of note, these studies have all been performed in vitro, often in DRG cultured neurons, and the involvement of similar factors in TRPM8 regulation in vivo still requires verification.…”

Section: Discussionmentioning

confidence: 99%

Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells

Kurose

Meng

2013

Journal of Neurophysiology

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Kurose M, Meng ID. Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells. J Neurophysiol 110: 495-504, 2013. First published May 1, 2013 doi:10.1152/jn.00222.2013.-Dry eye syndrome is a painful condition caused by inadequate or altered tear film on the ocular surface. Primary afferent cool cells innervating the cornea regulate the ocular fluid status by increasing reflex tearing in response to evaporative cooling and hyperosmicity. It has been proposed that activation of corneal cool cells via a transient receptor potential melastatin 8 (TRPM8) channel agonist may represent a potential therapeutic intervention to treat dry eye. This study examined the effect of dry eye on the response properties of corneal cool cells and the ability of the TRPM8 agonist menthol to modify these properties. A unilateral dry eye condition was created in rats by removing the left lacrimal gland. Lacrimal gland removal reduced tears in the dry eye to 35% compared with the contralateral eye and increased the number of spontaneous blinks in the dry eye by over 300%. Extracellular single-unit recordings were performed 8 -10 wk following surgery in the trigeminal ganglion of dry eye animals and age-matched controls. Responses of corneal cool cells to cooling were examined after the application of menthol (10 M-1.0 mM) to the ocular surface. The peak frequency of discharge to cooling was higher and the cooling threshold was warmer in dry eye animals compared with controls. The dry condition also altered the neuronal sensitivity to menthol, causing desensitization to cold-evoked responses at concentrations that produced facilitation in control animals. The mentholinduced desensitization of corneal cool cells would likely result in reduced tearing, a deleterious effect in individuals with dry eye.

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Section: Discussionmentioning

confidence: 99%

Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells

Kurose

Meng

2013

Journal of Neurophysiology

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“…The activity of TRPM8 is regulated by a number of cellular signaling pathways, most notably by phosphoinositides and the activation of phospholipase C (17). However, the cellular signaling pathways regulated by sM8α in prostate cancer cells are unclear.…”

Section: A B C Dmentioning

confidence: 99%

Overexpression of short TRPM8 variant α promotes cell migration and invasion, and decreases starvation-induced apoptosis in prostate cancer LNCaP cells

et al. 2015

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Abstract. The aim of the present study was to investigate the function of a transient receptor potential melastatin 8 (TRPM8) splice variant, short TRMP8α (sM8α), in the androgen-dependent prostate cancer LNCaP cell line, and to evaluate the potential involvement of the mitogen-activated protein kinase (MAPK) signaling pathway. The coding DNA for sM8α was cloned and transfected into LNCaP cells to generate cells that overexpress this isoform of TRPM8. Cellular proliferation was determined by performing an MTT assay, and flow cytometry was used to analyze apoptosis and cell cycle distribution. Furthermore, cellular migration and invasion were evaluated using Transwell ® migration assays. The subcellular location of recombinant sM8α was detected by quantum dots-based immunofluorescent imaging, western blotting was performed to examine the expression levels of proteins in the MAPK signaling pathway and reverse transcription-polymerase chain reaction was used to determine the expression of sM8α mRNA transcripts. The present study demonstrated that sM8α mRNA was expressed at a low level in the LNCaP, DU145 and PC-3 prostate cancer cell lines. Additionally, the recombinant sM8α protein was located in the cytoplasm of LNCaP cells and its overexpression significantly reduced starvation-induced apoptosis in these cells (P<0.05), possibly by means of reduced activation of phosphorylated-c-Jun N-terminal kinase (p-JNK). The migration and invasion of the LNCaP cells were markedly enhanced by the overexpression of sM8α, possibly via activation of MMP-2. Furthermore, overexpression of sM8α in LNCaP cells did not alter the expression of full-length TRPM8 and had no effect on cellular proliferation. Overall, the results of the present study indicate that sM8α may be important in the regulation of prostate cancer cell migration and invasion through the activation of matrix metalloproteinase-2, as well as in the regulation of apoptosis through the activation of p-JNK in the MAPK signaling pathway.

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“…223 Undoubtedly, the most studied endogenous TRPM8 regulatory mechanism is its dependence on PI(4,5)P 2 . 31 It is well documented that PI(4,5)P 2 modulates both activation and desensitization of the channel.…”

Section: Endogenous Regulation Of Trpm8mentioning

confidence: 99%

“…First, it has been documented its regulation by phospholipase A 2 (PLA 2 ), an enzyme that generates lysophospholipids and arachidonic acid. 223 Intriguingly, these lipids modulate TRPM8 activity in some cellular systems but not in planar lipid bilayers. A plausible explanation is that PLA 2 generates two antagonistic compounds as lysophospholipids tend to enhance TRPM8 activity and arachidonic acid inhibits the channel function.…”

Section: Endogenous Regulation Of Trpm8mentioning

confidence: 99%

Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer

et al. 2016

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Abstract. TRPM8 ion channels, the primary cold sensors in humans, are activated by innocuous cooling (< 28 ºC) and cooling compounds (menthol, icilin), and are implicated in sensing unpleasant cold stimuli, as well as in mammalian thermoregulation. Over-expression of these thermoregulators in prostate cancer and in other life-threatening tumors, along with their contribution to an increasing number of pathological conditions, opens a plethora of medicinal chemistry opportunities to develop receptor modulators. This Perspective seeks to compile current known modulators for this ion channel, since both agonists and antagonists may be useful for the treatment of most TRPM8-mediated pathologies. We primarily focus on SAR data for the different families of compounds and the pharmacological properties of the most promising ligands. Furthermore, we also address the knowledge about the channel structure, although still in its infancy, and the role of the TRPM8 protein signalplex to channel function and dysfunction. We finally outline the potential future prospects of the challenging TRPM8 drug discovery field.

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Regulation of TRPM8 channel activity

Cited by 70 publications

References 89 publications

Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells

Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells

Overexpression of short TRPM8 variant α promotes cell migration and invasion, and decreases starvation-induced apoptosis in prostate cancer LNCaP cells

Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer

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