title: Structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs.
abstract: The transient receptor potential vanilloid 1 (TRPV1) ion channel is a polymodal protein that responds to various stimuli, including capsaicin (the pungent compound found in chili peppers), extracellular acid, and basic intracellular pH, temperatures close to 42 °C, and several lipids. Lysophosphatidic acid (LPA), an endogenous lipid widely associated with neuropathic pain, is an agonist of the TRPV1 channel found in primary afferent nociceptors and is activated by other noxious stimuli. Agonists or antagonists of lipid and other chemical natures are known to possess specific structural requirements for producing functional effects on their targets. To better understand how LPA and other lipid analogs might interact and affect the function of TRPV1, we set out to determine the structural features of these lipids that result in the activation of TRPV1. By changing the acyl chain length, saturation, and headgroup of these LPA analogs, we established strict requirements for activation of TRPV1. Among the natural LPA analogs, we found that only LPA 18:1, alkylglycerophosphate 18:1, and cyclic phosphatidic acid 18:1, all with a monounsaturated C18 hydrocarbon chain activate TRPV1, whereas polyunsaturated and saturated analogs do not. Thus, TRPV1 shows a more restricted ligand specificity compared with LPA G-protein-coupled receptors. We synthesized fatty alcohol phosphates and thiophosphates and found that many of them with a single double bond in position Δ9, 10, or 11 and Δ9 cyclopropyl group can activate TRPV1 with efficacy similar to capsaicin. Finally, we developed a pharmacophore and proposed a mechanistic model for how these lipids could induce a conformational change that activates TRPV1.
authors.affiliation: From the Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F. 04510, México.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Morales-Lázaro
authors.affiliation: From the Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F. 04510, México.
authors.forename: Barbara
authors.initials: B
authors.lastname: Serrano-Flores
authors.affiliation: From the Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F. 04510, México.
authors.forename: Itzel
authors.initials: I
authors.lastname: Llorente
authors.affiliation: From the Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F. 04510, México.
authors.forename: Enrique
authors.initials: E
authors.lastname: Hernández-García
authors.affiliation: the Departmento de Biología Molecular e Histocompatibilidad, Hospital General "Dr. Manuel Gea González", México, D.F. 14080, México.
authors.forename: Ricardo
authors.initials: R
authors.lastname: González-Ramírez
authors.affiliation: the Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Souvik
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: the Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Duane
authors.initials: D
authors.lastname: Miller
authors.affiliation: RxBio Inc., Memphis, Tennessee 38163, and.
authors.forename: Veeresh
authors.initials: V
authors.lastname: Gududuru
authors.affiliation: the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: James
authors.initials: J
authors.lastname: Fells
authors.affiliation: the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Derek
authors.initials: D
authors.lastname: Norman
authors.affiliation: the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.affiliation: From the Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F. 04510, México.
authors.forename: Diana
authors.initials: D
authors.lastname: Escalante-Alcalde
authors.affiliation: From the Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F. 04510, México, trosenba@ifc.unam.mx.
authors.forename: Tamara
authors.initials: T
authors.lastname: Rosenbaum
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D050916:TRPV Cation Channels / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008246:Lysophospholipids; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C032881:lysophosphatidic acid
keywords: Ion Channel; Lysophospholipid; Membrane Lipid; Physiology; Transient Receptor Potential Channels (TRP Channels)