title: Nicotinic acid activates the capsaicin receptor TRPV1: Potential mechanism for cutaneous flushing.
abstract: OBJECTIVE
  Nicotinic acid (also known as niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment because of a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study, we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response on consumption of spicy food.
  
  
  RESULTS
  We observed that the nicotinic acid-induced increase in blood flow was substantially reduced in Trpv1(-/-) knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1.
  
  
  CONCLUSIONS
  Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and to improve compliance.
authors.affiliation: From the Department of Physiology and Membrane Biology (L.M., B.H.L., J.Z.) and Division of Cardiovascular Medicine (H.C., S.S.), University of California School of Medicine, Davis; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan Province, China (R.M, A.C., Y.J., L.X.); and Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia (L.M.).
authors.forename: Linlin
authors.initials: L
authors.lastname: Ma
authors.affiliation: From the Department of Physiology and Membrane Biology (L.M., B.H.L., J.Z.) and Division of Cardiovascular Medicine (H.C., S.S.), University of California School of Medicine, Davis; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan Province, China (R.M, A.C., Y.J., L.X.); and Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia (L.M.).
authors.forename: Bo Hyun
authors.initials: BH
authors.lastname: Lee
authors.affiliation: From the Department of Physiology and Membrane Biology (L.M., B.H.L., J.Z.) and Division of Cardiovascular Medicine (H.C., S.S.), University of California School of Medicine, Davis; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan Province, China (R.M, A.C., Y.J., L.X.); and Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia (L.M.).
authors.forename: Rongrong
authors.initials: R
authors.lastname: Mao
authors.affiliation: From the Department of Physiology and Membrane Biology (L.M., B.H.L., J.Z.) and Division of Cardiovascular Medicine (H.C., S.S.), University of California School of Medicine, Davis; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan Province, China (R.M, A.C., Y.J., L.X.); and Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia (L.M.).
authors.forename: Anping
authors.initials: A
authors.lastname: Cai
authors.affiliation: From the Department of Physiology and Membrane Biology (L.M., B.H.L., J.Z.) and Division of Cardiovascular Medicine (H.C., S.S.), University of California School of Medicine, Davis; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan Province, China (R.M, A.C., Y.J., L.X.); and Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia (L.M.).
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Jia
authors.affiliation: From the Department of Physiology and Membrane Biology (L.M., B.H.L., J.Z.) and Division of Cardiovascular Medicine (H.C., S.S.), University of California School of Medicine, Davis; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan Province, China (R.M, A.C., Y.J., L.X.); and Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia (L.M.).
authors.forename: Heather
authors.initials: H
authors.lastname: Clifton
authors.affiliation: From the Department of Physiology and Membrane Biology (L.M., B.H.L., J.Z.) and Division of Cardiovascular Medicine (H.C., S.S.), University of California School of Medicine, Davis; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan Province, China (R.M, A.C., Y.J., L.X.); and Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia (L.M.).
authors.forename: Saul
authors.initials: S
authors.lastname: Schaefer
authors.affiliation: From the Department of Physiology and Membrane Biology (L.M., B.H.L., J.Z.) and Division of Cardiovascular Medicine (H.C., S.S.), University of California School of Medicine, Davis; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan Province, China (R.M, A.C., Y.J., L.X.); and Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia (L.M.).
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: From the Department of Physiology and Membrane Biology (L.M., B.H.L., J.Z.) and Division of Cardiovascular Medicine (H.C., S.S.), University of California School of Medicine, Davis; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan Province, China (R.M, A.C., Y.J., L.X.); and Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia (L.M.). jzheng@ucdavis.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D002211:Capsaicin / Q000378:metabolism / Q000494:pharmacology; D005483:Flushing / Q000209:etiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009525:Niacin / Q000378:metabolism / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000187:drug effects / Q000502:physiology*
chemical_list: D001896:Boron Compounds; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D009525:Niacin; C109986:2-aminoethoxydiphenyl borate; D002211:Capsaicin
keywords: cardiovascular diseases; ion channels; lipoproteins; vasodilation