Pore helix domain is critical to camphor sensitivity of transient receptor potential vanilloid 1 channel.
BACKGROUND
The recent discovery that camphor activates and strongly desensitizes the capsaicin-sensitive and noxious heat-sensitive channel transient receptor potential vanilloid subfamily member 1 (TRPV1) has provided new insights and opened up new research paths toward understanding why this naturally occurring monoterpene is widely used in human medicine for its local counter-irritant, antipruritic, and anesthetic properties. However, the molecular basis for camphor sensitivity remains mostly unknown. The authors attempt to explore the nature of the activation pathways evoked by camphor and narrow down a putative interaction site at TRPV1.


METHODS
The authors transiently expressed wild-type or specifically mutated recombinant TRPV1 channels in human embryonic kidney cells HEK293T and recorded cation currents with the whole cell, patch clamp technique. To monitor changes in the spatial distribution of phosphatidylinositol 4,5-bisphosphate, they used fluorescence resonance energy transfer measurements from cells transfected with the fluorescent protein-tagged pleckstrin homology domains of phospholipase C.


RESULTS
The results revealed that camphor modulates TRPV1 channel through the outer pore helix domain by affecting its overall gating equilibrium. In addition, camphor, which generally is known to decrease the fluidity of cell plasma membranes, may also regulate the activity of TRPV1 by inducing changes in the spatial distribution of phosphatidylinositol-4,5-bisphosphate on the inner leaflet of the plasma membrane.


CONCLUSIONS
The findings of this study provide novel insights into the structural basis for the modulation of TRPV1 channel by camphor and may provide an explanation for the mechanism by which camphor modulates thermal sensation in vivo.
Department of Cellular Neurophysiology, Institute of Physiology, Academy of Sciences of Czech Republic, Videnska, Czech Republic.
Lenka
L
Marsakova
Filip
F
Touska
Jan
J
Krusek
Viktorie
V
Vlachova
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002164:Camphor / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D022022:Nuclear Pore / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*
D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D002164:Camphor