Molecular Mechanisms of TRPV1 Channel Activation

Abstract

Transient Receptor Potential (TRP) cation channels participate in various fundamental processes in cell-and organism-physiology in unicellular eukaryotes, invertebrates and vertebrates. Interestingly, many TRP channels function as detectors of sensory stimuli. The TRPV1 (vanilloid 1) channel serves as an integrator of noxious chemical and physical stimuli known to cause irritation and pain, such as elevated temperatures, acids, and irritant chemical compounds, and its activation has been linked to acute nociceptive pain and neurogenic inflammation. The mechanisms by which the channel detects incoming stimuli, how the sensing domains are coupled to channel gating and how these processes are connected to specific structural regions in the channel are not fully understood, but valuable information is available. Many sites involved in agonist detection have been characterized and gating models that describe many features of the channel's behavior have been put forward. Structural and functional information indicates TRP channels are similar to voltage-activated potassium channels, with a tetrameric organization and six-transmembrane-region subunits, a pore domain with multi-ion binding properties and an intracellular S6 gate that seems to be the point of convergence of the many activation modalities leading to the opening of the ion conduction pathway. Furthermore, TRPV1 expression is altered in various disease states and TRPV1 gene polymorphism was speculated to play a role in pain sensation. The complex activation and regulation of TRPV1 may have important implications for drug development.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…[Na + ] e negatively regulates the gating and polymodal sensitization of the TRPV1 channel (Ohta et al, 2008). To note, molecular mechanisms of TRPV1 activation were recently reviewed in Jara- Oseguera et al (2010).…”

Therapeutic Targeting of TRPV1 by Resiniferatoxin, from Preclinical Studies to Clinical Trials

“…anandamide, arachidonic acid metabolites as exemplified by N-arachidonoyldopamine Fig. (1), and 12-hydroperoxyeicosatetraenoic acid), and a variety of pungent plant products as exemplified by capsaicin (responsible for the piquancy of hot chilli peppers), resiniferatoxin (from E. resinifera), piperine (the pungent ingredient in black pepper), gingerol and zingerone (from ginger), and eugenol (a powerful essential oil found in cloves) [reviewed in [33][34]. Interestingly, TRPV1 is also activated venoms from jellyfish [35] and spiders [36].…”

“…Interestingly, TRPV1 is also activated venoms from jellyfish [35] and spiders [36]. In addition, TRPV1 is regulated by pro-inflammatory agents such bradykinin, adenosine triphosphate (ATP), protease activate receptor 2 (PAR-2), and nerve growth factor (NGF) [reviewed in [32][33][34]. These agents cause allosteric modification of the TRPV1 channel protein such that the probability of channel opening by heat, protons and capsaicin is enhanced [37].…”

Whirlin increases TRPV1 channel expression and cellular stability

“…Transient receptor potential vanilloid 1 (TRPV1) is a thermosensory channel activated by physical and chemical stimuli (1). This ion channel was initially described as the sensor for noxious temperatures (>42°C) and vanilloid molecules such as capsaicin (2).…”