Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea

Parra, Andrés; Madrid, Rodolfo; Echevarrı́a, Diego; Olmo, S. del; Morenilla‐Palao, Cruz; Acosta, M. Carmen; Gallar, Juana; Dhaka, Ajay; Viana, Félix; Belmonte, Carlos

doi:10.1038/nm.2264

Cited by 267 publications

(352 citation statements)

References 20 publications

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“…1 B). A similar effect was observed when the bicyclic system modification involves changes in the electronic nature of the ring (14) or an increase in ring size (18). In addition, tryptamine benzyl derivatives 19 and 20 lost the agonistic activity shown by the methylated analogue 4.…”

Section: Screening Of the Activity Of The Synthesized Compounds By Casupporting

confidence: 55%

“…The non-substituted N-1 indole derivatives (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) were quite productive. A direct linkage of the amine moiety with different bulky aromatic groups, such as naphthalene and quinolines, gives compounds 8-11 unable to act as TRPM8 modulators ( Figures 1A and 1B).…”

Section: Screening Of the Activity Of The Synthesized Compounds By Camentioning

confidence: 99%

“…12 Finally, TRPM8 modulators could be of interest in treating dry eye syndrome and excessive lacrimation dysfunction, due to extensive TRPM8 expression in corneal afferent neurons. 13,14 For these reasons, increasing efforts have been dedicated, both by academia and industry, to the design of TRPM8 ligands starting from different structural scaffolds. [15][16][17][18][19][20][21][22] Most of the compounds described in the literature showed high potency on TRPM8 channels, although they also show agonistic and/or antagonistic properties towards other TRP receptors, such as TRPA1 and TRPV1 channels.…”

Section: Introductionmentioning

confidence: 99%

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Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

et al. 2016

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Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach mainly for the treatment of pain. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. As a result of a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl) ethanamine, compound 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl) ethanamine, compound 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC 50 = 40±4 µM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentrationdependent inhibition of menthol-induced TRPM8 currents (IC 50 = 367±24 nM). Molecular modelling studies using a homology model of a single TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing two different binding modes for the agonist and the antagonist.

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Section: Screening Of the Activity Of The Synthesized Compounds By Casupporting

confidence: 55%

Section: Screening Of the Activity Of The Synthesized Compounds By Camentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

et al. 2016

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“…Skin-nerve preparations allow stimulation of isolated receptive fields of single C-and Aδ-fibers in mouse skin while recording propagated action potentials extracellularly (29,30). Extensive prior work in mammals established three types of coldsensitive afferent fibers: mechanosensitive C-fibers (nociceptors, C-mechano; CM), cold receptors (C-cold; CC), and mechanosensitive Aδ-fibers (Aδ-nociceptors) (31)(32)(33)(34)(35)(36)(37). In the mouse, CM-fibers can be subdivided further into two cold-sensitive subclasses, the cold nociceptors (C-mechano cold, CMC) and the multimodal cold nociceptors (C-mechano-cold-heat, CMCH) (29).…”

Section: Trpc5mentioning

confidence: 99%

“…In the mouse, CM-fibers can be subdivided further into two cold-sensitive subclasses, the cold nociceptors (C-mechano cold, CMC) and the multimodal cold nociceptors (C-mechano-cold-heat, CMCH) (29). In primates, CMC-and CMCH-fibers are believed to relay information to the brain that is perceived as painful cold, whereas CC-fibers are likely associated with innocuous cold (33,35).…”

Section: Trpc5mentioning

confidence: 99%

Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system

Zimmermann

Lennerz

Hein³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

193

165

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Detection and adaptation to cold temperature is crucial to survival. Cold sensing in the innocuous range of cold (>10-15°C) in the mammalian peripheral nervous system is thought to rely primarily on transient receptor potential (TRP) ion channels, most notably the menthol receptor, TRPM8. Here we report that TRP cation channel, subfamily C member 5 (TRPC5), but not TRPC1/TRPC5 heteromeric channels, are highly cold sensitive in the temperature range 37-25°C. We found that TRPC5 is present in mouse and human sensory neurons of dorsal root ganglia, a substantial number of peripheral nerves including intraepithelial endings, and in the dorsal lamina of the spinal cord that receives sensory input from the skin, consistent with a potential TRPC5 function as an innocuous cold transducer in nociceptive and thermosensory nerve endings. Although deletion of TRPC5 in 129S1/SvImJ mice resulted in no temperature-sensitive behavioral changes, TRPM8 and/or other menthol-sensitive channels appear to underpin a much larger component of noxious cold sensing after TRPC5 deletion and a shift in mechanosensitive C-fiber subtypes. These findings demonstrate that highly cold-sensitive TRPC5 channels are a molecular component for detection and regional adaptation to cold temperatures in the peripheral nervous system that is distinct from noxious cold sensing.pain | single-fiber | thermo-transient receptor potential | nociception | temperature sensing N ociceptors and thermoreceptive neurons, such as cold and heat receptors, innervate the skin and deep tissues. The cell bodies of sensory nerve endings are clustered in ganglia located in the vertebral column and cranium. Their projections extend to the skin where they arborize in terminals embedded between keratinocytes. Although nociceptors are polymodal and respond to stimuli (cold, heat, pressure, and noxious chemicals) that are capable of producing tissue damage and pain (1), cold receptors are unimodal and specialized to detect cool and cold temperatures (2). Transient receptor potential (TRP) ion channels are principal transducers of thermal stimuli that depolarize nerve terminals to the action potential threshold. Action potentials then relay the sensory information to integrative centers in the spinal cord and brain.All proteins are temperature sensitive, but most ion channels exhibit two-to threefold increases in gating with a 10°C change in temperature (Q 10 = 2-3). Certain ion channels exhibit dramatic temperature sensitivity in gating over physiologically relevant ranges (Q 10 = 10-30). Mammalian ion channels with such high Q 10 values include particular two-pore K + channels (3), the voltage-gated proton channel (4), transient receptor potential cation channel subfamily V members 1-3 (TRPV1-3) (5-7), transient receptor potential menthol receptor 8 (TRPM8) (8), and in some reports, TRP cation channel subfamily A member 1 (TRPA1) (9, 10). There is no a priori requirement for cold encoding by high Q 10 channels-action potential firing rates are affected perforce by temperature,...

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Sensory and sympathetic innervation of the mouse and guinea pig corneal epithelium

Ivanusic

Wood

Brock

2013

J of Comparative Neurology

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This study used immunohistochemistry, retrograde tracing, and high-resolution confocal microscopy to explore the structure and neurochemistry of nerve terminals in the corneal epithelium of mice and guinea pigs. In both species, sub-basal nerves formed a plexus in the basal epithelium. Some axons had bulbar endings within the basal epithelium, but most projected perpendicularly from sub-basal nerves to within a few micrometers of the epithelial surface. Three morphologies for these nerve terminals were identified. Simple terminals did not branch after leaving the sub-basal nerves and ended with a single, bulbar swelling. Ramifying terminals branched in the squamous cell layer, forming horizontal fibers that ran parallel to the surface and terminated with single bulbar swellings. Complex terminals branched as they approached the epithelial surface, forming a cluster of highly branched fibers with multiple bulbar endings. Calcitonin gene-related peptide immunolabeled (peptidergic) axons ended mostly in simple terminals, whereas transient receptor potential cation channel subfamily M member 8 immunolabeled (cold receptor) axons ended almost exclusively in complex terminals. Retrograde labeling identified discrete subpopulations of corneal afferent neurons in the trigeminal ganglion. Tyrosine hydroxylase-immunolabeled (sympathetic) nerve terminals originating from the superior cervical ganglion occurred throughout the corneal epithelium of mice, but only in the basal epithelium of guinea pigs. These findings demonstrate that nerve terminals in the corneal epithelium of mice and guinea pigs can be distinguished on the basis of their morphology and neurochemistry, and suggest that nerve terminals with different sensory modalities can be defined on the basis of their morphology.

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Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea

Cited by 267 publications

References 20 publications

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system

Sensory and sympathetic innervation of the mouse and guinea pig corneal epithelium

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