TRP Channels as Potential Drug Targets

Moran, Magdalene M.

doi:10.1146/annurev-pharmtox-010617-052832

Cited by 176 publications

(148 citation statements)

References 173 publications

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“…Regarding the potential of therapeutically targeting neuro-immune pathways, recent studies have shown that an anti-IL-31 receptor antibody, nemolizumab, successfully improves pruritus in patients with atopic dermatitis (77). Furthermore, ion channels play an essential role in the activation of sensory neurons, and TRP channel inhibitors are also promising candidates for various neuron-related symptoms and diseases (78). Neuropeptides, neurotransmitters, or their receptors are also potential targets for neuro-immune interaction, including VIP, CGRP, substance P, NMU, β2AR, and nAChR.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Neuro-immune crosstalk and allergic inflammation

Kabata¹,

Artis²

2019

Journal of Clinical Investigation

129

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The central nervous system (CNS) and peripheral tissues are connected by the peripheral nervous system (PNS), which transmitsThe neuronal and immune systems exhibit bidirectional interactions that play a critical role in tissue homeostasis, infection, and inflammation. Neuron-derived neuropeptides and neurotransmitters regulate immune cell functions, whereas inflammatory mediators produced by immune cells enhance neuronal activation. In recent years, accumulating evidence suggests that peripheral neurons and immune cells are colocalized and affect each other in local tissues. A variety of cytokines, inflammatory mediators, neuropeptides, and neurotransmitters appear to facilitate this crosstalk and positivefeedback loops between multiple types of immune cells and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems. In this Review, we discuss these recent findings regarding neuro-immune crosstalk that are uncovering molecular mechanisms that regulate inflammation. Finally, neuro-immune crosstalk has a key role in the pathophysiology of allergic diseases, and we present evidence indicating that neuro-immune interactions regulate asthma pathophysiology through both direct and indirect mechanisms.

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Section: Summary and Future Directionsmentioning

confidence: 99%

Neuro-immune crosstalk and allergic inflammation

Kabata¹,

Artis²

2019

Journal of Clinical Investigation

129

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“…TRP channels are activated and inhibited by a range of mechanisms, in response to thermal or chemical stimuli and/or mechanical forces (Venkatachalam and Montell, 2007). TRP channel mutations have been implicated in a number of different diseases (Nilius and Owsianik, 2010) and consequently are of interest as potential drug targets (Moran, 2018). Several TRP channels are modulated by membrane lipids (see for example (Fine et al, 2018;Wilkes et al, 2017;Yin et al, 2019), suggesting the possibility of lipid based therapies (Ciardo and Ferrer-Montiel, 2017).…”

Section: Introductionmentioning

confidence: 99%

Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2 (PC2)

Wang

Hedger

Aryal

et al. 2019

Preprint

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Polycystin-2 (PC2) is a member of the TRPP subfamily of TRP channels and is present in ciliary membranes of the kidney. PC2 can be either homo-tetrameric, or heterotetrameric with PC1. PC2 shares a common transmembrane fold with other TRP channels, in addition to having a novel extracellular domain. Several TRP channels have been suggested to be regulated by lipids, including phosphatidylinositol phosphates (PIPs). We have combined molecular dynamics simulations with cryoelectron microscopy to explore possible lipid interactions sites on PC2. We propose that PC2 has a PIP-binding site close to the equivalent vanilloid/lipid-binding site in the TRPV1 channel. A 3.0 Å cryoelectron microscopy map reveals a binding site for cholesterol on PC2. Cholesterol interactions with the channel at this site are further characterized by MD simulations. These results help to position PC2 within an emerging model of the complex roles of lipids in the regulation and organization of ciliary membranes.

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“…Therefore, sophisticated physiological and ecological mechanisms have been developed through evolution to first detect and then adapt to ambient temperature (3)(4)(5). The transient receptor potential melastatin 8 (TRPM8) channel is the prototypical sensor for cold in vertebrates (6,7), which has been validated in both knockout mice (8) and pharmacological studies (9). However, how cold activates TRPM8 remains obscure.…”

mentioning

confidence: 99%

A paradigm of thermal adaptation in penguins and elephants by tuning cold activation in TRPM8

Yang

Wang

et al. 2020

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

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To adapt to habitat temperature, vertebrates have developed sophisticated physiological and ecological mechanisms through evolution. Transient receptor potential melastatin 8 (TRPM8) serves as the primary sensor for cold. However, how cold activates TRPM8 and how this sensor is tuned for thermal adaptation remain largely unknown. Here we established a molecular framework of how cold is sensed in TRPM8 with a combination of patch-clamp recording, unnatural amino acid imaging, and structural modeling. We first observed that the maximum cold activation of TRPM8 in eight different vertebrates (i.e., African elephant and emperor penguin) with distinct side-chain hydrophobicity (SCH) in the pore domain (PD) is tuned to match their habitat temperature. We further showed that altering SCH for residues in the PD with solventaccessibility changes leads to specific tuning of the cold response in TRPM8. We also observed that knockin mice expressing the penguin's TRPM8 exhibited remarkable tolerance to cold. Together, our findings suggest a paradigm of thermal adaptation in vertebrates, where the evolutionary tuning of the cold activation in the TRPM8 ion channel through altering SCH and solvent accessibility in its PD largely contributes to the setting of the cold-sensitive/ tolerant phenotype.TRPM8 | cold activation | pore domain | side-chain hydrophobicity | thermal adaptation T o survive and thrive, all living beings have to perceive and adapt to ambient temperature (1), which varies over a wide range from below −50°C in polar areas to above 50°C in deserts (2). Therefore, sophisticated physiological and ecological mechanisms have been developed through evolution to first detect and then adapt to ambient temperature (3-5). The transient receptor potential melastatin 8 (TRPM8) channel is the prototypical sensor for cold in vertebrates (6, 7), which has been validated in both knockout mice (8) and pharmacological studies (9). However, how cold activates TRPM8 remains obscure. From the perspective of channel structure, an earlier study suggested that its C terminus is crucial for cold activation (10), while subsequent work demonstrated that the transmembrane core domain (5) or the pore domain (11) is essential for setting cold response. Although high-resolution structures of TRPM8 have been resolved by cryoelectron microscopy in both the apo and ligand-bound states (12-14), its coldactivated state structure is still unavailable. From the perspective of thermodynamics, large enthalpic (ΔH) and entropic (ΔS) changes are associated with TRPM8 cold activation (15,16). Changes in heat capacity have also been hypothesized to mediate cold activation (17), though experimental evidence for such a hypothesis is limited to voltage-gated potassium channels (18). Interestingly, cold activation of TRPM8 is tuned during evolution in several tested vertebrate species (5,11,19). To understand both the structural and thermodynamic bases of TRPM8 cold activation, we attempted to gain insights from TRPM8 orthologs in vertebrate species inhabiti...

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TRP Channels as Potential Drug Targets

Cited by 176 publications

References 173 publications

Neuro-immune crosstalk and allergic inflammation

Neuro-immune crosstalk and allergic inflammation

Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2 (PC2)

A paradigm of thermal adaptation in penguins and elephants by tuning cold activation in TRPM8

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