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