tailieunhanh - Báo cáo khoa học: Molecular architecture of the vanilloid receptor Insights for drug design

The transient receptor potential channel vanilloid receptor subunit 1 (TRPV1) is amolecular integrator of physical and chemical stimuli in the peripheral nociceptor terminals. TRPV1 is an ionotropic channel that plays a critical role in both thermal nociception and inflammatoryhyperalgesia. Structure–function relationships are providing fundamental insights of the modular architecture of this neuronal recep-tor. As a result, the molecular determinants that endow TRPV1 with its physiological properties, namely activation byheat, potentiation byextracellular acidic pH, and inter-action with vanilloid-like compounds, as well as its per-meation properties are being unveiled | Eur. J. Biochem. 271 1820-1826 2004 FEBS 2004 doi MINIREVIEW Molecular architecture of the vanilloid receptor Insights for drug design Antonio Ferrer-Montiel Carolina Garcia-Martinez Cruz Morenilla-Palao Nuria Garcia-Sanz Asia Fernandez-Carvajal Gregorio Fernandez-Ballester and Rosa Planells-Cases Instituto de Biologia Molecular y Celular Universidad Miguel Hernandez Alicante Spain The transient receptor potential channel vanilloid receptor subunit 1 TRPV1 is a molecular integrator of physical and chemical stimuli in the peripheral nociceptor terminals. TRPV1 is an ionotropic channel that plays a critical role in both thermal nociception and inflammatory hyperalgesia. Structure-function relationships are providing fundamental insights of the modular architecture of this neuronal receptor. As a result the molecular determinants that endow TRPV1 with its physiological properties namely activation byheat potentiation byextracellular acidic pH and interaction with vanilloid-like compounds as well as its permeation properties are being unveiled. This information can now be used to build up molecular models for the protein which upon experimental validation could be used as tools to thrust the target-oriented design of druggable TRPV1 ligands. Introduction The somatosensory symm a able to discriminate with extraordinary precision a id ranee of environmernal cues 1 and references therein . Sensory transduction is a complex biological process aimed at integrating and decoding physical and chemical stimuli. Furthermore sensoryperception of potentiallyharmful stimuli functions as a warning mechanism to avert potential tissue organ damage. The detection of painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons known as nociceptors 1 . These neurons have membrane receptors that act as sensitive sensors for changes in the physical and chemical habitat. These molecular devices endow nociceptors with remarkable