title: The chimeric approach reveals that differences in the TRPV1 pore domain determine species-specific sensitivity to block of heat activation.
abstract: The capsaicin-, heat-, and proton-activated ion channel TRPV1, a member of the transient receptor potential cation channel family is a polymodal nociceptor. For almost a decade, TRPV1 has been explored by the pharmaceutical industry as a potential target for example for pain conditions. Antagonists which block TRPV1 activation by capsaicin, heat, and protons were developed by a number of pharmaceutical companies. The unexpected finding of hyperthermia as an on-target side effect in clinical studies using polymodal TRPV1 antagonists has prompted companies to search for ways to circumvent hyperthermia, for example by the development of modality-selective antagonists. The significant lack of consistency of the pharmacology of many TRPV1 antagonists across different species has been a further obstacle. JYL-1421 for example was shown to block capsaicin and heat responses in human and monkey TRPV1 while it was largely ineffective in blocking heat responses in rat TRPV1. These findings suggested structural dissimilarities between different TRPV1 species relevant for small compound antagonism for example of heat activation. Using a chimeric approach (human and rat TRPV1) in combination with a novel FLIPR-based heat activation assay and patch-clamp electrophysiology we have identified the pore region as being strongly linked to the observed species differences. We demonstrate that by exchanging the pore domains JYL-1421, which is modality-selective in rat can be made modality-selective in human TRPV1 and vice-versa.
authors.affiliation: Pain Research Unit, Pfizer Global Research and Development, CT139NJ Sandwich, United Kingdom. thouli23@yahoo.co.uk
authors.forename: Marianthi
authors.initials: M
authors.lastname: Papakosta
authors.forename: Carine
authors.initials: C
authors.lastname: Dalle
authors.forename: Alison
authors.initials: A
authors.lastname: Haythornthwaite
authors.forename: Lishuang
authors.initials: L
authors.lastname: Cao
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stevens
authors.forename: Gillian
authors.initials: G
authors.lastname: Burgess
authors.forename: Rachel
authors.initials: R
authors.lastname: Russell
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cox
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Phillips
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C466314:JYL 1421; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; D013890:Thiourea