title: Farnesyl pyrophosphate is a novel pain-producing molecule via specific activation of TRPV3.
abstract: Temperature-sensitive transient receptor potential ion channels (thermoTRPs) expressed in epidermal keratinocytes and sensory afferents play an important role as peripheral pain detectors for our body. Many natural and synthetic compounds have been found to act on the thermoTRPs leading to altered nociception, but little is known about endogenous painful molecules activating TRPV3. Here, we show that farnesyl pyrophosphate (FPP), an intermediate metabolite in the mevalonate pathway, specifically activates TRPV3 among six thermoTRPs using Ca(2+) imaging and electrophysiology with cultured keratinocytes and TRPV3-overexpressing cells. Agonistic potencies of related compounds in the FPP metabolism were ignorable. Voltage-dependence of TRPV3 was shifted by FPP, which appears to be the activation mechanism. An intraplantar injection of FPP acutely elicits nociceptive behaviors in inflamed animals, indicating that FPP is a novel endogenous pain-producing substance via TRPV3 activation. Co-culture experiments demonstrated that this FPP-evoked signal in the keratinocytes is transmitted to sensory neurons. In addition, FPP reduced TRPV3 heat threshold resulting in heightened behavioral sensitivity to noxious heat. Taken together, our data suggest that FPP is the firstly identified endogenous TRPV3 activator that causes nociception. Our results may provide useful chemical information to elucidate TRPV3 physiology and novel pain-related metabolisms.
authors.affiliation: Korea University Graduate School of Medicine, Seoul 136-705, Korea.
authors.forename: Sangsu
authors.initials: S
authors.lastname: Bang
authors.forename: Sungjae
authors.initials: S
authors.lastname: Yoo
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Yang
authors.forename: Hawon
authors.initials: H
authors.lastname: Cho
authors.forename: Sun Wook
authors.initials: SW
authors.lastname: Hwang
mesh_terms: D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010146:Pain / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D012717:Sesquiterpenes / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*; D013696:Temperature
chemical_list: D008024:Ligands; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D050916:TRPV Cation Channels; C459445:TRPV3 protein, human; C004808:farnesyl pyrophosphate; D002118:Calcium
references.citation: J Biol Chem. 2004 Aug 20;279(34):35741-8
references.pmid: 15194687
references.citation: Br J Pharmacol. 2007 Jun;151(4):530-40
references.pmid: 17420775
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1626-31
references.pmid: 19164517
references.citation: J Invest Dermatol. 2009 Mar;129(3):714-22
references.pmid: 18754035
references.citation: Ann N Y Acad Sci. 2007 Nov;1117:209-57
references.pmid: 18056045
references.citation: Science. 2005 Mar 4;307(5714):1468-72
references.pmid: 15746429
references.citation: Biochem J. 2004 Jun 1;380(Pt 2):329-38
references.pmid: 14967069
references.citation: Cell. 1995 Jun 2;81(5):687-93
references.pmid: 7774010
references.citation: J Invest Dermatol. 2006 Dec;126(12):2664-72
references.pmid: 16858425
references.citation: Support Care Cancer. 2008 Oct;16(10):1105-15
references.pmid: 18682990
references.citation: Anal Biochem. 2008 Dec 1;383(1):18-24
references.pmid: 18782552
references.citation: Biochem Biophys Res Commun. 2008 May 30;370(2):295-300
references.pmid: 18371303
references.citation: Mol Pharmacol. 2009 Jun;75(6):1262-79
references.pmid: 19297520
references.citation: Nat Neurosci. 2006 May;9(5):628-35
references.pmid: 16617338
references.citation: Neurosci Lett. 2007 Sep 25;425(2):120-5
references.pmid: 17850966
references.citation: J Cell Physiol. 2006 Jul;208(1):201-12
references.pmid: 16557504
references.citation: Nature. 2002 Jul 11;418(6894):181-6
references.pmid: 12077604
references.citation: Anal Biochem. 1997 Oct 1;252(1):89-95
references.pmid: 9324945
references.citation: Curr Opin Anaesthesiol. 2006 Oct;19(5):566-72
references.pmid: 16960493
references.citation: J Neurosci. 2008 Dec 17;28(51):13727-37
references.pmid: 19091963
references.citation: J Neurosci. 2005 Sep 28;25(39):8924-37
references.pmid: 16192383
references.citation: Mol Pharmacol. 2003 Oct;64(4):785-95
references.pmid: 14500734
references.citation: J Neurosci. 2004 Jun 2;24(22):5177-82
references.pmid: 15175387
references.citation: Biochim Biophys Acta. 2006 Dec;1761(12):1506-14
references.pmid: 17092771
references.citation: Eur J Neurosci. 2007 Nov;26(9):2516-23
references.pmid: 17970723
references.citation: J Biol Chem. 2008 Mar 7;283(10):6162-74
references.pmid: 18178557
references.citation: Prog Brain Res. 2000;129:21-38
references.pmid: 11098679
references.citation: Nature. 2002 Jul 11;418(6894):186-90
references.pmid: 12077606
references.citation: Pflugers Arch. 2009 Oct;458(6):1093-102
references.pmid: 19669158
references.citation: J Biol Chem. 2008 Jul 25;283(30):21054-64
references.pmid: 18499677
references.citation: Science. 2002 Jun 14;296(5575):2046-9
references.pmid: 12016205
references.citation: Mol Cells. 2009 Apr 30;27(4):417-22
references.pmid: 19390822
references.citation: PLoS One. 2008 May 07;3(5):e2082
references.pmid: 18461159
references.citation: FASEB J. 2008 Aug;22(8):3024-34
references.pmid: 18492727
references.citation: J Physiol. 1999 May 15;517 ( Pt 1):181-92
references.pmid: 10226158
references.citation: Nat Chem Biol. 2006 Nov;2(11):596-607
references.pmid: 16998480
references.citation: Mol Cell Neurosci. 2006 Aug;32(4):335-43
references.pmid: 16829128