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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

Structural features of the capsaicin receptor. (A) Conserved structural domains: Ankyrin repeat domain—Olive. Pre-TM1 helix—Salmon. TM1-TM4 domain—Pale pink. TM4-TM5 linker—Cyan. Selectivity filter—Green. Gate—Fuchsia. TM5-TM6 domain—Yellow. TRP domain—Orange. (B) Residues involved in ligand-binding and/or modulation of channel activity: Colors represent residues location. TM1-TM4 domain—Fuchsia. Selectivity filter and pore helix—Green. TM5-TM6 domain—Yellow. Intracellular loops—Orange. Extracellular loops—Red. (C) Putative ligand-binding sites: Vanilloids—Red. Fatty acids and lipids—Green. PIP2—Cyan. Cysteine residues—Yellow. TRPV1 structure (PDB ID 3J5P) was visualized and colored using PyMOL Molecular Graphics System.
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Figure 1: Structural features of the capsaicin receptor. (A) Conserved structural domains: Ankyrin repeat domain—Olive. Pre-TM1 helix—Salmon. TM1-TM4 domain—Pale pink. TM4-TM5 linker—Cyan. Selectivity filter—Green. Gate—Fuchsia. TM5-TM6 domain—Yellow. TRP domain—Orange. (B) Residues involved in ligand-binding and/or modulation of channel activity: Colors represent residues location. TM1-TM4 domain—Fuchsia. Selectivity filter and pore helix—Green. TM5-TM6 domain—Yellow. Intracellular loops—Orange. Extracellular loops—Red. (C) Putative ligand-binding sites: Vanilloids—Red. Fatty acids and lipids—Green. PIP2—Cyan. Cysteine residues—Yellow. TRPV1 structure (PDB ID 3J5P) was visualized and colored using PyMOL Molecular Graphics System.

Mentions: Phylogenetic studies, transmembrane segment prediction, and structural data indicates that TRP channels are related to the superfamily of voltage-gated cation channels, for example voltage-gated potassium (Kv) and voltage-gated calcium (Cav) channels (Phillips et al., 1992; Wes et al., 1995; Harteneck et al., 2000; Ramsey et al., 2006; Liao et al., 2013). Biochemical, optical, and structural information support the notion of a tetrameric channel architecture (Jahnel et al., 2001; Kedei, 2001; Amiri et al., 2003; Veliz et al., 2010; Liao et al., 2013). TRP channels are diverse in their design and numerous structural features vary between members of different sub-families. However, the functional TRP channel is formed by the coassembly of four subunits, each comprising six transmembrane-spanning (TM) helices with intracellular amino- and carboxyl-terminus domains (Harteneck et al., 2000). By analogy to the 6TM architecture of Kv channels, TM5 and TM6 constitute the pore region. Electrophysiological and structural data further support this topology (Owsianik et al., 2006; Susankova et al., 2007; Salazar et al., 2009; Liao et al., 2013; Figure 1A). Since TRP channels are considered distant relatives of Kv channels and elicit voltage-dependent activation (zd = 0.4e − 0.9e), the TM1-TM4 region has been suggested to serve as a voltage-sensing domain (VSD) (Voets et al., 2007; Boukalova et al., 2013). However, chimeras between TRPM8, TRPV1, and Kv1.2 in which TM1-TM4 of TRPM8, and TRPV1 is replaced with TM1-TM4 of Kv1.2 produced non-functional TRP channels suggesting that the Kv1.2 VSD is insufficient to restore TRP channel function (Kalia and Swartz, 2013). The structure of TRPV1 lacks a patch of charged amino acids, located in the TM1-TM4 domain, typically associated with voltage-sensitivity in Kv channels. Thus, evidence indicates that TRP channels likely utilize a different mechanism to sense voltage. Given a hypothetical scenario in which the TM1-TM4 domain behaves statically, as it apparently does when ligands or toxins bind to the channel (Cao et al., 2013b), it is probably not TM1-TM4 but the pore region undergoing voltage-dependent structural rearrangements. It is important to note here that most of the work claiming voltage-dependent changes caused by mutagenesis underscore a shift in the conductance-voltage (G-V) curve along the voltage axis as an indication of voltage dependence. This should be taken with caution since this observation alone may suggest a direct effect on allosteric coupling rather than gating charge suppression.


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

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

Structural features of the capsaicin receptor. (A) Conserved structural domains: Ankyrin repeat domain—Olive. Pre-TM1 helix—Salmon. TM1-TM4 domain—Pale pink. TM4-TM5 linker—Cyan. Selectivity filter—Green. Gate—Fuchsia. TM5-TM6 domain—Yellow. TRP domain—Orange. (B) Residues involved in ligand-binding and/or modulation of channel activity: Colors represent residues location. TM1-TM4 domain—Fuchsia. Selectivity filter and pore helix—Green. TM5-TM6 domain—Yellow. Intracellular loops—Orange. Extracellular loops—Red. (C) Putative ligand-binding sites: Vanilloids—Red. Fatty acids and lipids—Green. PIP2—Cyan. Cysteine residues—Yellow. TRPV1 structure (PDB ID 3J5P) was visualized and colored using PyMOL Molecular Graphics System.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Structural features of the capsaicin receptor. (A) Conserved structural domains: Ankyrin repeat domain—Olive. Pre-TM1 helix—Salmon. TM1-TM4 domain—Pale pink. TM4-TM5 linker—Cyan. Selectivity filter—Green. Gate—Fuchsia. TM5-TM6 domain—Yellow. TRP domain—Orange. (B) Residues involved in ligand-binding and/or modulation of channel activity: Colors represent residues location. TM1-TM4 domain—Fuchsia. Selectivity filter and pore helix—Green. TM5-TM6 domain—Yellow. Intracellular loops—Orange. Extracellular loops—Red. (C) Putative ligand-binding sites: Vanilloids—Red. Fatty acids and lipids—Green. PIP2—Cyan. Cysteine residues—Yellow. TRPV1 structure (PDB ID 3J5P) was visualized and colored using PyMOL Molecular Graphics System.
Mentions: Phylogenetic studies, transmembrane segment prediction, and structural data indicates that TRP channels are related to the superfamily of voltage-gated cation channels, for example voltage-gated potassium (Kv) and voltage-gated calcium (Cav) channels (Phillips et al., 1992; Wes et al., 1995; Harteneck et al., 2000; Ramsey et al., 2006; Liao et al., 2013). Biochemical, optical, and structural information support the notion of a tetrameric channel architecture (Jahnel et al., 2001; Kedei, 2001; Amiri et al., 2003; Veliz et al., 2010; Liao et al., 2013). TRP channels are diverse in their design and numerous structural features vary between members of different sub-families. However, the functional TRP channel is formed by the coassembly of four subunits, each comprising six transmembrane-spanning (TM) helices with intracellular amino- and carboxyl-terminus domains (Harteneck et al., 2000). By analogy to the 6TM architecture of Kv channels, TM5 and TM6 constitute the pore region. Electrophysiological and structural data further support this topology (Owsianik et al., 2006; Susankova et al., 2007; Salazar et al., 2009; Liao et al., 2013; Figure 1A). Since TRP channels are considered distant relatives of Kv channels and elicit voltage-dependent activation (zd = 0.4e − 0.9e), the TM1-TM4 region has been suggested to serve as a voltage-sensing domain (VSD) (Voets et al., 2007; Boukalova et al., 2013). However, chimeras between TRPM8, TRPV1, and Kv1.2 in which TM1-TM4 of TRPM8, and TRPV1 is replaced with TM1-TM4 of Kv1.2 produced non-functional TRP channels suggesting that the Kv1.2 VSD is insufficient to restore TRP channel function (Kalia and Swartz, 2013). The structure of TRPV1 lacks a patch of charged amino acids, located in the TM1-TM4 domain, typically associated with voltage-sensitivity in Kv channels. Thus, evidence indicates that TRP channels likely utilize a different mechanism to sense voltage. Given a hypothetical scenario in which the TM1-TM4 domain behaves statically, as it apparently does when ligands or toxins bind to the channel (Cao et al., 2013b), it is probably not TM1-TM4 but the pore region undergoing voltage-dependent structural rearrangements. It is important to note here that most of the work claiming voltage-dependent changes caused by mutagenesis underscore a shift in the conductance-voltage (G-V) curve along the voltage axis as an indication of voltage dependence. This should be taken with caution since this observation alone may suggest a direct effect on allosteric coupling rather than gating charge suppression.

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