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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

The structure of natural and endovaniloids. (A) Natural compounds with agonist activity on TRPV1 receptors. Figure indicates the affinity for specific 3[H]-resiniferatoxin binding sites in rat spinal cord (Szallasi and Blumberg, 1999). (B) Structure of endovanilloids identified as activators of TRPV1 receptors.
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Figure 3: The structure of natural and endovaniloids. (A) Natural compounds with agonist activity on TRPV1 receptors. Figure indicates the affinity for specific 3[H]-resiniferatoxin binding sites in rat spinal cord (Szallasi and Blumberg, 1999). (B) Structure of endovanilloids identified as activators of TRPV1 receptors.

Mentions: Several naturally occurring compounds sharing structural similarities with capsaicin also augment the open probability of TRPV1 (Sterner and Szallasi, 1999; Vriens et al., 2008; Figures 3, 4). In this context, structure-activity relationship (SAR) analysis has proved to be a useful tool for understanding not only the effects of capsaicin's analogs, but also to find some structural requirements for competitive antagonism to inhibit the activation of TRPV1 receptors by exogenous and endogenous ligands (Walpole et al., 1993a,b,c; Planells-Cases et al., 2003; Kym et al., 2009). Capsaicin pharmacophore models (Figure 5A) consist of three parts named regions A, B, and C (Szallasi and Blumberg, 1999). In this model, recognition of the binding site is mediated by hydrogen bonds through vanillyl (region A) and amide (region B) groups. Hydrophobic interactions occur within region C through the linear aliphatic chain (3E)-2-methyloct-3-ene. These pharmacophoric features are frequently found in most of the identified agonists (Figure 5A) and antagonists (Figure 5B) of TRPV1 receptors. Activity measurements show that potency increases with highly polar functional groups in region B, for example urea and thiourea (Suh et al., 2005; Drizin et al., 2006). Evaluation of more restrictive conformations between regions B and C which consequently confer less flexibility to the linker connecting regions A and B (Figure 5C), enhance the antagonistic effect. Another important factor to consider is the critical role that bioactive conformations play in the design of novel drugs (Gore et al., 2007; Perner et al., 2010). The hypothesized bioactive conformations adopted for agonist and antagonist binding to TRPV1 channels show differences between the polar (B) and hydrophobic (C) regions. This observation helped the identification of several competitive antagonists, characterized by the presence of a heterocyclic system, which maintains the polar nature of region B and its ability to form hydrogen bonds (Jetter et al., 2008; Hawryluk et al., 2010).


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

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

The structure of natural and endovaniloids. (A) Natural compounds with agonist activity on TRPV1 receptors. Figure indicates the affinity for specific 3[H]-resiniferatoxin binding sites in rat spinal cord (Szallasi and Blumberg, 1999). (B) Structure of endovanilloids identified as activators of TRPV1 receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: The structure of natural and endovaniloids. (A) Natural compounds with agonist activity on TRPV1 receptors. Figure indicates the affinity for specific 3[H]-resiniferatoxin binding sites in rat spinal cord (Szallasi and Blumberg, 1999). (B) Structure of endovanilloids identified as activators of TRPV1 receptors.
Mentions: Several naturally occurring compounds sharing structural similarities with capsaicin also augment the open probability of TRPV1 (Sterner and Szallasi, 1999; Vriens et al., 2008; Figures 3, 4). In this context, structure-activity relationship (SAR) analysis has proved to be a useful tool for understanding not only the effects of capsaicin's analogs, but also to find some structural requirements for competitive antagonism to inhibit the activation of TRPV1 receptors by exogenous and endogenous ligands (Walpole et al., 1993a,b,c; Planells-Cases et al., 2003; Kym et al., 2009). Capsaicin pharmacophore models (Figure 5A) consist of three parts named regions A, B, and C (Szallasi and Blumberg, 1999). In this model, recognition of the binding site is mediated by hydrogen bonds through vanillyl (region A) and amide (region B) groups. Hydrophobic interactions occur within region C through the linear aliphatic chain (3E)-2-methyloct-3-ene. These pharmacophoric features are frequently found in most of the identified agonists (Figure 5A) and antagonists (Figure 5B) of TRPV1 receptors. Activity measurements show that potency increases with highly polar functional groups in region B, for example urea and thiourea (Suh et al., 2005; Drizin et al., 2006). Evaluation of more restrictive conformations between regions B and C which consequently confer less flexibility to the linker connecting regions A and B (Figure 5C), enhance the antagonistic effect. Another important factor to consider is the critical role that bioactive conformations play in the design of novel drugs (Gore et al., 2007; Perner et al., 2010). The hypothesized bioactive conformations adopted for agonist and antagonist binding to TRPV1 channels show differences between the polar (B) and hydrophobic (C) regions. This observation helped the identification of several competitive antagonists, characterized by the presence of a heterocyclic system, which maintains the polar nature of region B and its ability to form hydrogen bonds (Jetter et al., 2008; Hawryluk et al., 2010).

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