title: A novel biological role for the phospholipid lysophosphatidylinositol in nociceptive sensitization via activation of diverse G-protein signalling pathways in sensory nerves in vivo.
abstract: The rich diversity of lipids and the specific signalling pathways they recruit provides tremendous scope for modulation of biological functions. Lysophosphatidylinositol (LPI) is emerging as a key modulator of cell proliferation, migration, and function, and holds important pathophysiological implications due to its high levels in diseased tissues, such as in cancer. Here we report a novel role for LPI in sensitization of peripheral sensory neurons, which was evident as exaggerated sensitivity to painful and innocuous pressure. Histopathological analyses indicated lack of involvement of myelin pathology and immune cell recruitment by LPI. Using pharmacological and conditional genetic tools in mice, we delineated receptor-mediated from non-receptor-mediated effects of LPI and we observed that GPR55, which functions as an LPI receptor when heterologously expressed in mammalian cells, only partially mediates LPI-induced actions in the context of pain sensitization in vivo; we demonstrate that, in vivo, LPI functions by activating Gα(13) as well as Gα(q/11) arms of G-protein signalling in sensory neurons. This study thus reports a novel pathophysiological function for LPI and elucidates underlying molecular mechanisms.
authors: Institute of Pharmacology, Heidelberg University, Heidelberg 69120, Germany Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg 69120, Germany Max-Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany Department of Screening and Compound Profiling, Molecular Discovery Research, GlaxoSmithKline, Hertfordshire, UK.
authors: Vijayan
authors: V
authors: Gangadharan
authors: Deepitha
authors: D
authors: Selvaraj
authors: Martina
authors: M
authors: Kurejova
authors: Christian
authors: C
authors: Njoo
authors: Simon
authors: S
authors: Gritsch
authors: Dagmar
authors: D
authors: Škoricová
authors: Heinz
authors: H
authors: Horstmann
authors: Stefan
authors: S
authors: Offermanns
authors: Andrew J
authors: AJ
authors: Brown
authors: Thomas
authors: T
authors: Kuner
authors: Anke
authors: A
authors: Tappe-Theodor
authors: Rohini
authors: R
authors: Kuner
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010743:Phospholipids / Q000494:pharmacology / Q000502:physiology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D008246:Lysophospholipids; D010743:Phospholipids; C025449:lysophosphatidylinositol; D019204:GTP-Binding Proteins; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: Cancer pain; G-proteins; GPR55; LPI; Peripheral sensitization
references: Agarwal N, Offermanns S, Kuner R. Conditional gene deletion in primary nociceptive neurons of trigeminal ganglia and dorsal root ganglia. Genesis. 2004;38:122-129.
references: Agarwal N, Pacher P, Tegeder I, Amaya F, Constantin CE, Brenner GJ, Rubino T, Michalski CW, Marsicano G, Monory K, Mackie K, Marian C, Batkai S, Parolaro D, Fischer MJ, Reeh P, Kunos G, Kress M, Lutz B, Woolf CJ, Kuner R. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci. 2007;10:870-879.
references: Aoki J, Taira A, Takanezawa Y, Kishi Y, Hama K, Kishimoto T, Mizuno K, Saku K, Taguchi R, Arai H. Serum lysophosphatidic acid is produced through diverse phospholipase pathways. J Biol Chem. 2002;277:48737-48744.
references: Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267-284.
references: Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature. 2007;448:204-208.
references: Bondarenko A, Waldeck-Weiermair M, Naghdi S, Poteser M, Malli R, Graier WF. GPR55-dependent and -independent ion signalling in response to lysophosphatidylinositol in endothelial cells. Br J Pharmacol. 2010;161:308-320.
references: Breen C, Brownjohn PW, Ashton JC. The atypical cannabinoid O-1602 increases hind paw sensitisation in the chronic constriction injury model of neuropathic pain. Neurosci Lett. 2012;508:119-122.
references: Constantin CE, Mair N, Sailer CA, Andratsch M, Xu ZZ, Blumer MJ, Scherbakov N, Davis JB, Bluethmann H, Ji RR, Kress M. Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model. J Neurosci. 2008;28:5072-5081.
references: Corda D, Iurisci C, Berrie CP. Biological activities and metabolism of the lysophosphoinositides and glycerophosphoinositols. Biochim Biophys Acta. 2002;1582:52-69.
references: Dai Y, Iwata K, Fukuoka T, Kondo E, Tokunaga A, Yamanaka H, Tachibana T, Liu Y, Noguchi K. Phosphorylation of extracellular signal-regulated kinase in primary afferent neurons by noxious stimuli and its involvement in peripheral sensitization. J Neurosci. 2002;22:7737-7745.
references: Falasca M, Corda D. Elevated levels and mitogenic activity of lysophosphatidylinositol in k-ras-transformed epithelial cells. Eur J Biochem. 1994;221:383-389.
references: Falasca M, Silletta MG, Carvelli A, Di Francesco AL, Fusco A, Ramakrishna V, Corda D. Signalling pathways involved in the mitogenic action of lysophosphatidylinositol. Oncogene. 1995;10:2113-2124.
references: Ford LA, Roelofs AJ, Anavi-Goffer S, Mowat L, Simpson DG, Irving AJ, Rogers MJ, Rajnicek AM, Ross RA. A role for l-alpha-lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells. Br J Pharmacol. 2010;160:762-771.
references: Gangadharan V, Wang R, Ulzhofer B, Luo C, Bardoni R, Bali KK, Agarwal N, Tegeder I, Hildebrandt U, Nagy GG, Todd AJ, Ghirri A, Haussler A, Sprengel R, Seeburg PH, MacDermott AB, Lewin GR, Kuner R. Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice. J Clin Invest. 2011;121:1608-1623.
references: Hartmann B, Ahmadi S, Heppenstall PA, Lewin GR, Schott C, Borchardt T, Seeburg PH, Zeilhofer HU, Sprengel R, Kuner R. The AMPA receptor subunits GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain. Neuron. 2004;44:637-650.
references: Henstridge CM, Balenga NA, Ford LA, Ross RA, Waldhoer M, Irving AJ. The GPR55 ligand l-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB J. 2009;23:183-193.
references: Henstridge CM, Balenga NA, Schroder R, Kargl JK, Platzer W, Martini L, Arthur S, Penman J, Whistler JL, Kostenis E, Waldhoer M, Irving AJ. GPR55 ligands promote receptor coupling to multiple signalling pathways. Br J Pharmacol. 2010;160:604-614.
references: Inoue M, Rashid MH, Fujita R, Contos JJ, Chun J, Ueda H. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat Med. 2004;10:712-718.
references: Ji RR, Baba H, Brenner GJ, Woolf CJ. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci. 1999;2:1114-1119.
references: Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001;413:203-210.
references: Korhonen H, Fisslthaler B, Moers A, Wirth A, Habermehl D, Wieland T, Schutz G, Wettschureck N, Fleming I, Offermanns S. Anaphylactic shock depends on endothelial Gq/G11. J Exp Med. 2009;206:411-420.
references: Kuner R. Central mechanisms of pathological pain. Nat Med. 2010;16:1258-1266.
references: Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci USA. 2008;105:2699-2704.
references: Lechner SG, Lewin GR. Peripheral sensitisation of nociceptors via G-protein-dependent potentiation of mechanotransduction currents. J Physiol. 2009;587:3493-3503.
references: Leffler A, Linte RM, Nau C, Reeh P, Babes A. A high-threshold heat-activated channel in cultured rat dorsal root ganglion neurons resembles TRPV2 and is blocked by gadolinium. Eur J Neurosci. 2007;26:12-22.
references: Maingret F, Patel AJ, Lesage F, Lazdunski M, Honore E. Lysophospholipids open the two-pore domain mechano-gated K(+) channels TREK-1 and TRAAK. J Biol Chem. 2000;275:10128-10133.
references: Monet M, Gkika D, Lehen’kyi V, Pourtier A, Vanden Abeele F, Bidaux G, Juvin V, Rassendren F, Humez S, Prevarsakaya N. Lysophospholipids stimulate prostate cancer cell migration via TRPV2 channel activation. Biochim Biophys Acta. 2009;1793:528-539.
references: Obara Y, Ueno S, Yanagihata Y, Nakahata N. Lysophosphatidylinositol causes neurite retraction via GPR55, G13 and RhoA in PC12 cells. PLoS One. 2011;6:e24284.
references: Oka S, Kimura S, Toshida T, Ota R, Yamashita A, Sugiura T. Lysophosphatidylinositol induces rapid phosphorylation of p38 mitogen-activated protein kinase and activating transcription factor 2 in HEK293 cells expressing GPR55 and IM-9 lymphoblastoid cells. J Biochem. 2010;147:671-678.
references: Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T. Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun. 2007;362:928-934.
references: Pineiro R, Falasca M. Lysophosphatidylinositol signalling: new wine from an old bottle. Biochim Biophys Acta. 2012;1821:694-705.
references: Rau KK, Jiang N, Johnson RD, Cooper BY. Heat sensitization in skin and muscle nociceptors expressing distinct combinations of TRPV1 and TRPV2 protein. J Neurophysiol. 2007;97:2651-2662.
references: Reeh PW. Sensory receptors in mammalian skin in an in vitro preparation. Neurosci Lett. 1986;66:141-146.
references: Ross RA. l-alpha-lysophosphatidylinositol meets GPR55: a deadly relationship. Trends Pharmacol Sci. 2011;32:265-269.
references: Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152:1092-1101.
references: Schuelert N, McDougall JJ. The abnormal cannabidiol analogue O-1602 reduces nociception in a rat model of acute arthritis via the putative cannabinoid receptor GPR55. Neurosci Lett. 2011;500:72-76.
references: Schweizerhof M, Stösser S, Kurejova M, Njoo C, Gangadharan V, Agarwal N, Schmelz M, Bali KK, Michalski CW, Brugger S, Dickenson A, Simone DA, Kuner R. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nat Med. 2009;15:802-807.
references: Shen Z, Wu M, Elson P, Kennedy AW, Belinson J, Casey G, Xu Y. Fatty acid composition of lysophosphatidic acid and lysophosphatidylinositol in plasma from patients with ovarian cancer and other gynecological diseases. Gynecol Oncol. 2001;83:25-30.
references: Soga T, Ohishi T, Matsui T, Saito T, Matsumoto M, Takasaki J, Matsumoto S, Kamohara M, Hiyama H, Yoshida S, Momose K, Ueda Y, Matsushime H, Kobori M, Furuichi K. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem Biophys Res Commun. 2005;326:744-751.
references: Staton PC, Hatcher JP, Walker DJ, Morrison AD, Shapland EM, Hughes JP, Chong E, Mander PK, Green PJ, Billinton A, Fulleylove M, Lancaster HC, Smith JC, Bailey LT, Wise A, Brown AJ, Richardson JC, Chessell IP. The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain. PAIN®. 2008;139:225-236.
references: Stösser S, Agarwal N, Tappe-Theodor A, Yanagisawa M, Kuner R. Dissecting the functional significance of endothelin A receptors in peripheral nociceptors in vivo via conditional gene deletion. PAIN®. 2010;148:206-214.
references: Sutphen R, Xu Y, Wilbanks GD, Fiorica J, Grendys EC Jr, LaPolla JP, Arango H, Hoffman MS, Martino M, Wakeley K, Griffin D, Blanco RW, Cantor AB, Xiao YJ, Krischer JP. Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2004;13:1185-1191.
references: Tappe-Theodor A, Constantin CE, Tegeder I, Lechner SG, Langeslag M, Lepcynzsky P, Wirotanseng RI, Kurejova M, Agarwal N, Nagy G, Todd A, Wettschureck N, Offermanns S, Kress M, Lewin GR, Kuner R. Galpha(q/11) signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization. PAIN®. 2011;153:184-196.
references: Ueda H. Peripheral mechanisms of neuropathic pain – involvement of lysophosphatidic acid receptor-mediated demyelination. Mol Pain. 2008;4:11.
references: Vanden Abeele F, Zholos A, Bidaux G, Shuba Y, Thebault S, Beck B, Flourakis M, Panchin Y, Skryma R, Prevarskaya N. Ca2+-independent phospholipase A2-dependent gating of TRPM8 by lysophospholipids. J Biol Chem. 2006;281:40174-40182.
references: Xiao YJ, Schwartz B, Washington M, Kennedy A, Webster K, Belinson J, Xu Y. Electrospray ionization mass spectrometry analysis of lysophospholipids in human ascitic fluids: comparison of the lysophospholipid contents in malignant vs nonmalignant ascitic fluids. Anal Biochem. 2001;290:302-313.
references: Zimmermann K, Hein A, Hager U, Kaczmarek JS, Turnquist BP, Clapham DE, Reeh PW. Phenotyping sensory nerve endings in vitro in the mouse. Nat Protoc. 2009;4:174-196.