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A structural view of ligand-dependent activation in thermoTRP channels.

Steinberg X, Lespay-Rebolledo C, Brauchi S - Front Physiol (2014)

Bottom Line: Sensitive to electric, chemical, mechanical, and thermal cues, TRP channels are tightly associated with the detection and integration of sensory input, emerging as a model to study the polymodal activation of ion channel proteins.Understanding the molecular mechanics underlying ligand-dependent modulation of TRP channels may help with the rational design of novel synthetic analgesics.The present review focuses on the structural basis of ligand-dependent activation of TRPV1 and TRPM8 channels.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, Institute of Physiology, Universidad Austral de Chile Campus Isla Teja, Valdivia, Chile ; Faculty of Sciences, Graduate School, Universidad Austral de Chile Campus Isla Teja, Valdivia, Chile.

ABSTRACT
Transient Receptor Potential (TRP) proteins are a large family of ion channels, grouped into seven sub-families. Although great advances have been made regarding the activation and modulation of TRP channel activity, detailed molecular mechanisms governing TRP channel gating are still needed. Sensitive to electric, chemical, mechanical, and thermal cues, TRP channels are tightly associated with the detection and integration of sensory input, emerging as a model to study the polymodal activation of ion channel proteins. Among TRP channels, the temperature-activated kind constitute a subgroup by itself, formed by Vanilloid receptors 1-4, Melastatin receptors 2, 4, 5, and 8, TRPC5, and TRPA1. Some of the so-called "thermoTRP" channels participate in the detection of noxious stimuli making them an interesting pharmacological target for the treatment of pain. However, the poor specificity of the compounds available in the market represents an important obstacle to overcome. Understanding the molecular mechanics underlying ligand-dependent modulation of TRP channels may help with the rational design of novel synthetic analgesics. The present review focuses on the structural basis of ligand-dependent activation of TRPV1 and TRPM8 channels. Special attention is drawn to the dissection of ligand-binding sites within TRPV1, PIP2-dependent modulation of TRP channels, and the structure of natural and synthetic ligands.

No MeSH data available.


Related in: MedlinePlus

Fatty acids and lipids as thermoTRP channel ligands. (A) Polyunsaturated fatty acids (PUFAs) evaluated on TRPV1 and TRPA1 receptors (Matta et al., 2007; Motter and Ahern, 2012). (B) 5-nitro-2-(3-phenylpropylamino) benzoic acid derivatives evaluated on TRPA1 receptors (Liu et al., 2010).
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Figure 6: Fatty acids and lipids as thermoTRP channel ligands. (A) Polyunsaturated fatty acids (PUFAs) evaluated on TRPV1 and TRPA1 receptors (Matta et al., 2007; Motter and Ahern, 2012). (B) 5-nitro-2-(3-phenylpropylamino) benzoic acid derivatives evaluated on TRPA1 receptors (Liu et al., 2010).

Mentions: Omega-3 polyunsaturated fatty acids (PUFAs) and some of their derivatives, for example farnesyl thiosalicylic acid (Maher et al., 2008) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) (Liu et al., 2010) are moderate agonists of TRPV1 (Matta et al., 2007) and TRPA1 (Motter and Ahern, 2012). Lipids bind differently on TRPV1 compared with capsaicin (Figure 1C). SAR analysis of PUFAs indicates that the aromatic ring is critical for their action. On the other hand, increasing unsaturation of the fatty acid polar domain promotes a more potent response (Figures 6A,B).


A structural view of ligand-dependent activation in thermoTRP channels.

Steinberg X, Lespay-Rebolledo C, Brauchi S - Front Physiol (2014)

Fatty acids and lipids as thermoTRP channel ligands. (A) Polyunsaturated fatty acids (PUFAs) evaluated on TRPV1 and TRPA1 receptors (Matta et al., 2007; Motter and Ahern, 2012). (B) 5-nitro-2-(3-phenylpropylamino) benzoic acid derivatives evaluated on TRPA1 receptors (Liu et al., 2010).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4017155&req=5

Figure 6: Fatty acids and lipids as thermoTRP channel ligands. (A) Polyunsaturated fatty acids (PUFAs) evaluated on TRPV1 and TRPA1 receptors (Matta et al., 2007; Motter and Ahern, 2012). (B) 5-nitro-2-(3-phenylpropylamino) benzoic acid derivatives evaluated on TRPA1 receptors (Liu et al., 2010).
Mentions: Omega-3 polyunsaturated fatty acids (PUFAs) and some of their derivatives, for example farnesyl thiosalicylic acid (Maher et al., 2008) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) (Liu et al., 2010) are moderate agonists of TRPV1 (Matta et al., 2007) and TRPA1 (Motter and Ahern, 2012). Lipids bind differently on TRPV1 compared with capsaicin (Figure 1C). SAR analysis of PUFAs indicates that the aromatic ring is critical for their action. On the other hand, increasing unsaturation of the fatty acid polar domain promotes a more potent response (Figures 6A,B).

Bottom Line: Sensitive to electric, chemical, mechanical, and thermal cues, TRP channels are tightly associated with the detection and integration of sensory input, emerging as a model to study the polymodal activation of ion channel proteins.Understanding the molecular mechanics underlying ligand-dependent modulation of TRP channels may help with the rational design of novel synthetic analgesics.The present review focuses on the structural basis of ligand-dependent activation of TRPV1 and TRPM8 channels.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, Institute of Physiology, Universidad Austral de Chile Campus Isla Teja, Valdivia, Chile ; Faculty of Sciences, Graduate School, Universidad Austral de Chile Campus Isla Teja, Valdivia, Chile.

ABSTRACT
Transient Receptor Potential (TRP) proteins are a large family of ion channels, grouped into seven sub-families. Although great advances have been made regarding the activation and modulation of TRP channel activity, detailed molecular mechanisms governing TRP channel gating are still needed. Sensitive to electric, chemical, mechanical, and thermal cues, TRP channels are tightly associated with the detection and integration of sensory input, emerging as a model to study the polymodal activation of ion channel proteins. Among TRP channels, the temperature-activated kind constitute a subgroup by itself, formed by Vanilloid receptors 1-4, Melastatin receptors 2, 4, 5, and 8, TRPC5, and TRPA1. Some of the so-called "thermoTRP" channels participate in the detection of noxious stimuli making them an interesting pharmacological target for the treatment of pain. However, the poor specificity of the compounds available in the market represents an important obstacle to overcome. Understanding the molecular mechanics underlying ligand-dependent modulation of TRP channels may help with the rational design of novel synthetic analgesics. The present review focuses on the structural basis of ligand-dependent activation of TRPV1 and TRPM8 channels. Special attention is drawn to the dissection of ligand-binding sites within TRPV1, PIP2-dependent modulation of TRP channels, and the structure of natural and synthetic ligands.

No MeSH data available.


Related in: MedlinePlus