Brain natriuretic peptide constitutively downregulates P2X3 receptors by controlling their phosphorylation state and membrane localization

Molecular Pain

Andrea Nistri²  Elsa Fabbretti¹  Sandra Vilotti²  Anna Marchenkova² 

[1] Center for Biomedical Sciences and Engineering, University of Nova Gorica, Nova Gorica, 5000, Slovenia;Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, Trieste, 34136, Italy

关键词: Sensory neuron;    Protein kinase G (PKG);    Lipid raft;    Purinergic signaling;    Purinergic receptor;    Pain;    ATP;    Trigeminal ganglia;   

Others  :  1234028
DOI  :  10.1186/s12990-015-0074-6

 received in 2015-09-10, accepted in 2015-11-03,  发布年份 2015

【 摘 要 】

Background

ATP-gated P2X3 receptors are important transducers of nociceptive stimuli and are almost exclusively expressed by sensory ganglion neurons. In mouse trigeminal ganglion (TG), P2X3 receptor function is unexpectedly enhanced by pharmacological block of natriuretic peptide receptor-A (NPR-A), outlining a potential inhibitory role of endogenous natriuretic peptides in nociception mediated by P2X3 receptors. Lack of change in P2X3 protein expression indicates a complex modulation whose mechanisms for downregulating P2X3 receptor function remain unclear.

Results

To clarify this process in mouse TG cultures, we suppressed NPR-A signaling with either siRNA of the endogenous agonist BNP, or the NPR-A blocker anantin. Thus, we investigated changes in P2X3 receptor distribution in the lipid raft membrane compartment, their phosphorylation state, as well as their function with patch clamping. Delayed onset of P2X3 desensitization was one mechanism for the anantin-induced enhancement of P2X3 activity. Anantin application caused preferential P2X3 receptor redistribution to the lipid raft compartment and decreased P2X3 serine phosphorylation, two phenomena that were not interdependent. An inhibitor of cGMP-dependent protein kinase and siRNA-mediated knockdown of BNP mimicked the effect of anantin.

Conclusions

We demonstrated that in mouse trigeminal neurons endogenous BNP acts on NPR-A receptors to determine constitutive depression of P2X3 receptor function. Tonic inhibition of P2X3 receptor activity by BNP/NPR-A/PKG pathways occurs via two distinct mechanisms: P2X3 serine phosphorylation and receptor redistribution to non-raft membrane compartments. This novel mechanism of receptor control might be a target for future studies aiming at decreasing dysregulated P2X3 receptor activity in chronic pain.

【 授权许可】

   
2015 Marchenkova et al.

【 图 表 】

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【 参考文献 】

• [1]Vulchanova L, Riedl MS, Shuster SJ, Buell G, Surprenant A, North RA, Elde R: Immunohistochemical study of the P2X2 and P2X3 receptor subunits in rat and monkey sensory neurons and their central terminals. Neuropharmacology 1997, 36:1229-1242.
• [2]Llewellyn-Smith IJ, Burnstock G: Ultrastructural localization of P2X3 receptors in rat sensory neurons. NeuroReport 1998, 9:2545-2550.
• [3]Wirkner K, Stanchev D, Köles L, Klebingat M, Dihazi H, Flehmig G, Vial C, Evans RJ, Fürst S, Mager PP, Eschrich K, Illes P: Regulation of human recombinant P2X3 receptors by ecto-protein kinase C. J Neurosci 2005, 25:7734-7742.
• [4]Burnstock G: Purinergic P2 receptors as targets for novel analgesics. Pharmacol Ther 2006, 110:433-454.
• [5]Giniatullin R, Nistri A, Fabbretti E: Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol Neurobiol 2008, 37:83-90.
• [6]Hullugundi SK, Ansuini A, Ferrari MD, van den Maagdenberg AMJM, Nistri A: A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1. Neuroscience 2014, 266:244-254.
• [7]Xu G-Y, Huang L-YM: Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J Neurosci 2002, 22:93-102.
• [8]Burnstock G: Purinergic signalling: pathophysiology and therapeutic potential. Keio J Med 2013, 62:63-73.
• [9]Fabbretti E, D’Arco M, Fabbro A, Simonetti M, Nistri A, Giniatullin R: Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J Neurosci 2006, 26:6163-6171.
• [10]Ma W, Quirion R: Targeting cell surface trafficking of pain-facilitating receptors to treat chronic pain conditions. Expert Opin Ther Targets 2014, 18:459-472.
• [11]Chen X-Q, Zhu J-X, Wang Y, Zhang X, Bao L: CaMKIIα and caveolin-1 cooperate to drive ATP-induced membrane delivery of the P2X3 receptor. J Mol Cell Biol 2014, 6:140-153.
• [12]D’Arco M, Giniatullin R, Leone V, Carloni P, Birsa N, Nair A, Nistri A, Fabbretti E: The C-terminal Src inhibitory kinase (Csk)-mediated tyrosine phosphorylation is a novel molecular mechanism to limit P2X3 receptor function in mouse sensory neurons. J Biol Chem 2009, 284:21393-21401.
• [13]Nair A, Simonetti M, Fabbretti E, Nistri A: The Cdk5 kinase downregulates ATP-gated ionotropic P2X3 receptor function via serine phosphorylation. Cell Mol Neurobiol 2010, 30:505-509.
• [14]Mo G, Grant R, O’Donnell D, Ragsdale DS, Cao CQ, Séguéla P: Neuropathic Nav1.3-mediated sensitization to P2X activation is regulated by protein kinase C. Mol Pain 2011, 7:14. BioMed Central Full Text
• [15]Giniatullin R, Nistri A: Desensitization properties of P2X3 receptors shaping pain signaling. Front Cell Neurosci 2013, 7:245.
• [16]Paukert M, Osteroth R, Geisler H-S, Brändle U, Glowatzki E, Ruppersberg JP, Gründer S: Inflammatory Mediators potentiate ATP-gated channels through the P2X3 subunit. J Biol Chem 2001, 276:21077-21082.
• [17]Chen Y, Zhang L, Yang J, Zhang L, Chen Z: LPS-induced dental pulp inflammation increases expression of ionotropic purinergic receptors in rat trigeminal ganglion. NeuroReport 2014, 25:991-997.
• [18]Schiavuzzo JG, Teixeira JM, Melo B, da Silva Dos Santos DF, Jorge CO, Oliveira-Fusaro MCG, Parada CA. Muscle hyperalgesia induced by peripheral P2X3 receptors is modulated by inflammatory mediators. Neuroscience. 2015;285:24–33.
• [19]Ellis A, Bennett DLH: Neuroinflammation and the generation of neuropathic pain. Br J Anaesth 2013, 111:26-37.
• [20]Nakagawa T, Wakamatsu K, Zhang N, Maeda S, Minami M, Satoh M, Kaneko S: Intrathecal administration of ATP produces long-lasting allodynia in rats: differential mechanisms in the phase of the induction and maintenance. Neuroscience 2007, 147:445-455.
• [21]Fabbretti E: ATP P2X3 receptors and neuronal sensitization. Front Cell Neurosci 2013, 7:236.
• [22]Yan J, Dussor G: Ion channels and migraine. Headache 2014, 54:619-639.
• [23]Liu X-Y, Wan L, Huo F-Q, Barry DM, Li H, Zhao Z-Q, Chen Z-F: B-type natriuretic peptide is neither itch-specific nor functions upstream of the GRP-GRPR signaling pathway. Mol Pain 2014, 10:4. BioMed Central Full Text
• [24]Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM. Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications. Handb Exp Pharmacol. 2009:341–366.
• [25]Misono KS: Natriuretic peptide receptor: structure and signaling. Mol Cell Biochem 2002, 230:49-60.
• [26]Vilotti S, Marchenkova A, Ntamati N, Nistri A: B-type natriuretic peptide-induced delayed modulation of TRPV1 and P2X3 receptors of mouse trigeminal sensory neurons. PLoS One 2013, 8:e81138.
• [27]Zhang F-X, Liu X-J, Gong L-Q, Yao J-R, Li K-C, Li Z-Y, Lin L-B, Lu Y-J, Xiao H-S, Bao L, Zhang X-H, Zhang X: Inhibition of inflammatory pain by activating B-type natriuretic peptide signal pathway in nociceptive sensory neurons. J Neurosci 2010, 30:10927-10938.
• [28]Fabbretti E, Nistri A: Regulation of P2X3 receptor structure and function. CNS Neurol Disord 2012, 11:687-698.
• [29]Vacca F, Amadio S, Sancesario G, Bernardi G, Volonté C: P2X3 receptor localizes into lipid rafts in neuronal cells. J Neurosci Res 2004, 76:653-661.
• [30]Zajchowski LD, Robbins SM: Lipid rafts and little caves. Compartmentalized signalling in membrane microdomains. Eur J Biochem 2002, 269:737-752.
• [31]Garcia-Marcos M, Dehaye J-P, Marino A: Membrane compartments and purinergic signalling: the role of plasma membrane microdomains in the modulation of P2XR-mediated signalling. FEBS J 2009, 276:330-340.
• [32]Allsopp RC, Lalo U, Evans RJ: Lipid raft association and cholesterol sensitivity of P2X1-4 receptors for ATP: chimeras and point mutants identify intracellular amino-terminal residues involved in lipid regulation of P2X1 receptors. J Biol Chem 2010, 285:32770-32777.
• [33]Sokolova E, Skorinkin A, Moiseev I, Agrachev A, Nistri A, Giniatullin R: Experimental and modeling studies of desensitization of P2X3 receptors. Mol Pharmacol 2006, 70:373-382.
• [34]Gnanasekaran A, Sundukova M, van den Maagdenberg AMJM, Fabbretti E, Nistri A: Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model. Mol Pain 2011, 7:77. BioMed Central Full Text
• [35]Cady RJ, Glenn JR, Smith KM, Durham PL: Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol Pain 2011, 7:94. BioMed Central Full Text
• [36]Yasuda M, Shinoda M, Kiyomoto M, Honda K, Suzuki A, Tamagawa T, Kaji K, Kimoto S, Iwata K: P2X3 receptor mediates ectopic mechanical allodynia with inflamed lower lip in mice. Neurosci Lett 2012, 528:67-72.
• [37]Simonetti M, Giniatullin R, Fabbretti E: Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons. J Biol Chem 2008, 283:18743-18752.
• [38]Ceruti S, Villa G, Fumagalli M, Colombo L, Magni G, Zanardelli M, Fabbretti E, Verderio C, van den Maagdenberg AMJM, Nistri A, Abbracchio MP: Calcitonin gene-related peptide-mediated enhancement of purinergic Neuron/Glia communication by the algogenic factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Cav2.1 Knock-In Mice: implications for basic mechanisms of migraine pain. J Neurosci 2011, 31:3638-3649.
• [39]Hullugundi SK, Ferrari MD, van den Maagdenberg AMJM, Nistri A: The mechanism of functional up-regulation of P2X3 receptors of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine type 1 (FHM-1). PLoS One 2013, 8:e60677.
• [40]Nair A, Simonetti M, Birsa N, Ferrari MD, van den Maagdenberg AMJM, Giniatullin R, Nistri A, Fabbretti E. Familial hemiplegic migraine Ca(v)2.1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain. Mol Pain. 2010;6:48.
• [41]Xu G-Y, Huang L-YM: Ca 2+ /calmodulin-dependent protein kinase II potentiates ATP responses by promoting trafficking of P2X receptors. Proc Natl Acad Sci USA 2004, 101:11868-11873.
• [42]Hofmann F, Feil R, Kleppisch T, Schlossmann J: Function of cGMP-dependent protein kinases as revealed by gene deletion. Physiol Rev 2006, 86:1-23.
• [43]Pandey KN. Guanylyl cyclase/natriuretic peptide receptor-A signaling antagonizes phosphoinositide hydrolysis, Ca2+ release, and activation of protein kinase C. Front Mol Neurosci. 2014;7.
• [44]Reger AS, Yang MP, Koide-Yoshida S, Guo E, Mehta S, Yuasa K, Liu A, Casteel DE, Kim C: Crystal structure of the cGMP-dependent protein kinase II leucine zipper and Rab11b protein complex reveals molecular details of G-kinase-specific interactions. J Biol Chem 2014, 289:25393-25403.
• [45]Potter LR: Regulation and therapeutic targeting of peptide-activated receptor guanylyl cyclases. Pharmacol Ther 2011, 130:71-82.
• [46]Pasdois P, Quinlan CL, Rissa A, Tariosse L, Vinassa B, Costa ADT, Pierre SV, Dos Santos P, Garlid KD: Ouabain protects rat hearts against ischemia-reperfusion injury via pathway involving src kinase, mitoKATP, and ROS. Am J Physiol Heart Circ Physiol 2007, 292:H1470-H1478.
• [47]Hidaka H, Kobayashi R: Pharmacology of protein kinase inhibitors. Annu Rev Pharmacol Toxicol 1992, 32:377-397.
• [48]Tsuda M, Koizumi S, Kita A, Shigemoto Y, Ueno S, Inoue K. Mechanical allodynia caused by intraplantar injection of P2X receptor agonist in rats: involvement of heteromeric P2X2/3 receptor signaling in capsaicin-sensitive primary afferent neurons. J Neurosci. 2000;20:RC90.
• [49]Kawashima E, Estoppey D, Virginio C, Fahmi D, Rees S, Surprenant A, North RA: A novel and efficient method for the stable expression of heteromeric ion channels in mammalian cells. Recept Channels 1998, 5:53-60.
• [50]Chen X, Gebhart GF: Differential purinergic signaling in bladder sensory neurons of naïve and bladder-inflamed mice. Pain 2010, 148:462-472.
• [51]Simonetti M, Fabbro A, D’Arco M, Zweyer M, Nistri A, Giniatullin R, Fabbretti E: Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin. Mol Pain 2006, 2:11. BioMed Central Full Text
• [52]Pike LJ: Rafts defined: a report on the keystone symposium on lipid rafts and cell function. J Lipid Res 2006, 47:1597-1598.
• [53]Lingwood D, Kaiser H-J, Levental I, Simons K: Lipid rafts as functional heterogeneity in cell membranes. Biochem Soc Trans 2009, 37(Pt 5):955-960.
• [54]D’Arco M, Giniatullin R, Simonetti M, Fabbro A, Nair A, Nistri A, Fabbretti E: Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons. J Neurosci 2007, 27:8190-8201.
• [55]Gnanasekaran A, Sundukova M, Hullugundi S, Birsa N, Bianchini G, Hsueh Y-P, Nistri A, Fabbretti E: Calcium/calmodulin-dependent serine protein kinase (CASK) is a new intracellular modulator of P2X3 receptors. J Neurochem 2013, 126:102-112.
• [56]Feil R, Hofmann F, Kleppisch T: Function of cGMP-dependent protein kinases in the nervous system. Rev Neurosci 2005, 16:23-41.
• [57]Schlossmann J, Desch M. cGK substrates. In: Schmidt HHHW, Hofmann F, Stasch J-P, editors. cGMP: Generators, effectors and therapeutic implications. Berlin, Heidelberg: Springer; 2009. pp. 163–93 (Handbook of Experimental Pharmacology, vol. 191).
• [58]Hofmann F, Bernhard D, Lukowski R, Weinmeister P. cGMP regulated protein kinases (cGK). Handb Exp Pharmacol. 2009:137–62.
• [59]Olesen J, Thomsen LL, Iversen H: Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci 1994, 15:149-153.
• [60]Pedersen SH, Ramachandran R, Amrutkar DV, Petersen S, Olesen J, Jansen-Olesen I. Mechanisms of glyceryl trinitrate provoked mast cell degranulation. Cephalalgia. 2015.
• [61]Messlinger K, Lennerz JK, Eberhardt M, Fischer MJM: CGRP and NO in the trigeminal system: mechanisms and role in headache generation. Headache 2012, 52:1411-1427.
• [62]Ramachandran R, Bhatt DK, Ploug KB, Hay-Schmidt A, Jansen-Olesen I, Gupta S, Olesen J: Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation. Cephalalgia 2014, 34:136-147.
• [63]Tvedskov JF, Tfelt-Hansen P, Petersen KA, Jensen LT, Olesen J: CGRP receptor antagonist olcegepant (BIBN4096BS) does not prevent glyceryl trinitrate-induced migraine. Cephalalgia 2010, 30:1346-1353.
• [64]Ohnishi T, Matsumura S, Ito S: Translocation of neuronal nitric oxide synthase to the plasma membrane by ATP is mediated by P2X and P2Y receptors. Mol Pain 2009, 5:40. BioMed Central Full Text
• [65]Tvedskov JF, Iversen HK, Olesen J, Tfelt-Hansen P: Nitroglycerin provocation in normal subjects is not a useful human migraine model? Cephalalgia 2010, 30:928-932.
• [66]Vulchanova L, Riedl MS, Shuster SJ, Stone LS, Hargreaves KM, Buell G, Surprenant A, North RA, Elde R: P2X3 is expressed by DRG neurons that terminate in inner lamina II. Eur J Neurosci 1998, 10:3470-3478.
• [67]Yu Y-C, Cao L-H, Yang X-L: Modulation by brain natriuretic peptide of GABA receptors on rat retinal ON-type bipolar cells. J Neurosci 2006, 26:696-707.
• [68]Jansen I, Mortensen A, Edvinsson L: Characterization of calcitonin gene-related peptide receptors in human cerebral vessels. Vasomotor responses and cAMP accumulation. Ann N Y Acad Sci 1992, 657:435-440.
• [69]Giniatullin R, Di Angelantonio S, Marchetti C, Sokolova E, Khiroug L, Nistri A: Calcitonin gene-related peptide rapidly downregulates nicotinic receptor function and slowly raises intracellular Ca 2+  in rat chromaffin cells in vitro. J Neurosci 1999, 19:2945-2953.
• [70]Chiba T, Yamaguchi A, Yamatani T, Nakamura A, Morishita T, Inui T, Fukase M, Noda T, Fujita T: Calcitonin gene-related peptide receptor antagonist human CGRP-(8–37). Am J Physiol 1989, 256(2 Pt 1):E331-E335.
• [71]Liu M, Huang W, Wu D, Priestley JV: TRPV1, but not P2X, requires cholesterol for its function and membrane expression in rat nociceptors. Eur J Neurosci 2006, 24:1-6.
• [72]Szoke E, Börzsei R, Tóth DM, Lengl O, Helyes Z, Sándor Z, Szolcsányi J: Effect of lipid raft disruption on TRPV1 receptor activation of trigeminal sensory neurons and transfected cell line. Eur J Pharmacol 2010, 628:67-74.
• [73]Ferrari U, Empl M, Kim KS, Sostak P, Förderreuther S, Straube A: Calcineurin inhibitor-induced headache: clinical characteristics and possible mechanisms. Headache 2005, 45:211-214.
• [74]Grotz WH, Breitenfeldt MK, Braune SW, Allmann KH, Krause TM, Rump JA, Schollmeyer PJ: Calcineurin-inhibitor induced pain syndrome (CIPS): a severe disabling complication after organ transplantation. Transpl Int 2001, 14:16-23.
• [75]Lyons WE, George EB, Dawson TM, Steiner JP, Snyder SH: Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia. Proc Natl Acad Sci USA 1994, 91:3191-3195.
• [76]Abdelalim EM, Tooyama I: BNP signaling is crucial for embryonic stem cell proliferation. PLoS One 2009, 4:e5341.
• [77]Franceschini A, Nair A, Bele T, van den Maagdenberg AM, Nistri A, Fabbretti E: Functional crosstalk in culture between macrophages and trigeminal sensory neurons of a mouse genetic model of migraine. BMC Neurosci 2012, 13:143. BioMed Central Full Text