The cannabinoid WIN55,212-2 protects against oxidized LDL-induced inflammatory response in murine macrophages

The endocannabinoid system has recently been attracted interest for its anti-inflammatory and anti-oxidative properties. In this study, we investigated the role of the endocannabinoid system in regulating the oxidized low-density lipoprotein (oxLDL)-induced inflammatory response in macrophages. RAW264.7 mouse macrophages and peritoneal macrophages isolated from Sprague-Dawley (SD) rats were exposed to oxLDL with or without the synthetic cannabinoid WIN55,212-2. To assess the inflammatory response, reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF- α) levels were determined, and activation of the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappa B signaling pathways were assessed. We observed that: i) oxLDL strongly induced ROS generation and TNF- α secretion in murine macrophages; ii) oxLDL-induced TNF- α and ROS levels could be lowered considerably by WIN55,212-2 via inhibition of MAPK (ERK1/2) signaling and NF-kappa B activity; and iii) the effects of WIN55212-2 were attenuated by the selective CB2 receptor antagonist AM630. These results demonstrate the involvement of the endocannabinoid system in regulating the oxLDL-induced inflammatory response in macrophages, and indicate that the CB2 receptor may offer a novel pharmaceutical target for treating atherosclerosis. The endocannabinoid system has recently been attracted interest for its anti-inflammatory and anti-oxidative properties. In this study, we investigated the role of the endocannabinoid system in regulating the oxidized low-density lipoprotein (oxLDL)-induced inflammatory response in macrophages. RAW264.7 mouse macrophages and peritoneal macrophages isolated from Sprague-Dawley (SD) rats were exposed to oxLDL with or without the synthetic cannabinoid WIN55,212-2. To assess the inflammatory response, reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF- α) levels were determined, and activation of the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappa B signaling pathways were assessed. We observed that: i) oxLDL strongly induced ROS generation and TNF- α secretion in murine macrophages; ii) oxLDL-induced TNF- α and ROS levels could be lowered considerably by WIN55,212-2 via inhibition of MAPK (ERK1/2) signaling and NF-kappa B activity; and iii) the effects of WIN55212-2 were attenuated by the selective CB2 receptor antagonist AM630. These results demonstrate the involvement of the endocannabinoid system in regulating the oxLDL-induced inflammatory response in macrophages, and indicate that the CB2 receptor may offer a novel pharmaceutical target for treating atherosclerosis. Atherosclerosis is no longer considered simply a lipid metabolism disorder, but rather, a subacute inflammatory condition of the vascular system. Although altered lipids levels play a role, they probably only represent part of the overall problem. Oxidation of low-density lipoproteins increases their atherogenicity (1.Steinberg D. Parthasarathy S. Carew T. Khoo J. Witztum J. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.N. Engl. J. Med. 1989; 320: 915-924Crossref PubMed Google Scholar). Accordingly, elevated plasma levels of oxidized low-density lipoprotein (oxLDL) are associated with coronary artery disease (2.Holvoet P. Vanhaecke J. Janssens S. Van de Werf F. Collen D. Oxidized LDL and malondialdehyde-modified LDL in patients with acute coronary syndromes and stable coronary artery disease.Circulation. 1998; 98: 1487-1494Crossref PubMed Scopus (597) Google Scholar). There is accumulating evidence that oxLDL binds the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), thereby stimulating endothelial cells to produce adhesion molecules and recruit leukocytes into the subintimal space. Concomitant pathological effects include an imbalance between NO generation and oxidative stress, endothelial dysfunction, proinflammatory changes to the vessel wall, foam cell formation, apoptosis of smooth muscle cells, and unstable and rupture-prone lesions (3.Ogura S. Kakino A. Sato Y. Fujita Y. Iwamoto S. Otsui K. Yoshimoto R. Sawamura T. LOX-1: the multifunctional receptor underlying cardiovascular dysfunction.Circ. J. 2009; 73: 1993-1999Crossref PubMed Scopus (90) Google Scholar). The endocannabinoid system has recently attracted interest for its anti-inflammatory and anti-oxidative effects in a number of chronic inflammatory diseases and disorders linked with organ ischemia/reperfusion (I/R) injury. Oxidative stimuli that appear to activate the endocannabinoid system include oxLDL (4.Jiang L.S. Pu J. Han Z.H. Hu L.H. He B. Role of activated endocannabinoid system in regulation of cellular cholesterol metabolism in macrophages.Cardiovasc. Res. 2009; 81: 805-813Crossref PubMed Scopus (49) Google Scholar), lipopolysaccharide (LPS) (5.Liu J. Wang L. Harvey-White J. Osei-Hyiaman D. Razdan R. Gong Q. Chan A.C. Zhou Z. Huang B.X. Kim H.Y. et al.A biosynthetic pathway for anandamide.Proc. Natl. Acad. Sci. USA. 2006; 103: 13345-13350Crossref PubMed Scopus (359) Google Scholar), hydrogen peroxide, and tumor necrosis factor-α (TNF-α) (6.Bátkai S. Osei-Hyiaman D. Pan H. El-Assal O. Rajesh M. Mukhopadhyay P. Hong F. Harvey-White J. Jafri A. Haskó G. et al.Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury.FASEB J. 2007; 21: 1788-1800Crossref PubMed Scopus (219) Google Scholar). Further, studies have reported that activation of the CB2 cannabinoid receptor protects against myocardial (7.Di Filippo C. Rossi F. Rossi S. D'Amico M. Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia- reperfusion injury: involvement of cytokine/chemokines and PMN.J. Leukoc. Biol. 2004; 75: 453-459Crossref PubMed Scopus (111) Google Scholar), hepatic (6.Bátkai S. Osei-Hyiaman D. Pan H. El-Assal O. Rajesh M. Mukhopadhyay P. Hong F. Harvey-White J. Jafri A. Haskó G. et al.Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury.FASEB J. 2007; 21: 1788-1800Crossref PubMed Scopus (219) Google Scholar), and cerebral (8.Ashton J.C. Rahman R.M. Nair S.M. Sutherland B.A. Glass M. Appleton I. Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain.Neurosci. Lett. 2007; 412: 114-117Crossref PubMed Scopus (113) Google Scholar) I/R injury due to its anti-inflammatory and anti-oxidative properties. Specifically, Defer et al. (9.Defer N. Wan J. Souktani R. Escoubet B. Perier M. Caramelle P. Manin S. Deveaux V. Bourin M.C. Zimmer A. et al.The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy.FASEB J. 2009; 23: 2120-2130Crossref PubMed Scopus (100) Google Scholar) reported that CB2 activation promotes cardiac myocyte and fibroblast survival and protects against I/R injury-induced cardiomyopathy. In contrast, CB1 cannabinoid receptor activation activates p38 mitogen-activated protein kinase (MAPK) signaling, thereby mediating reactive oxygen species (ROS) production and the synthesis of TNF-α and monocyte chemoattractant protein-1 (MCP-1), which are negatively regulated by CB2 via Rap1 (10.Han K.H. Lim S. Ryu J. Lee C.W. Kim Y. Kang J.H. Kang S.S. Ahn Y.K. Park C.S. Kim J.J. CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages.Cardiovasc. Res. 2009; 84: 378-386Crossref PubMed Scopus (162) Google Scholar). Important cross talk has been revealed between inflammation, generation of reactive oxygen and nitrogen species, and lipid metabolism in the pathogenesis of atherosclerosis. A recent study by Bátkai (11.Bátkai S. Rajesh M. Mukhopadhyay P. Haskó G. Liaudet L. Cravatt B.F. Csiszár A. Ungvári Z. Pacher P. Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase.Am. J. Physiol. Heart Circ. Physiol. 2007; 293: H909-H918Crossref PubMed Scopus (89) Google Scholar) demonstrated that the endocannabinoid neurotransmitter anandamide (AEA) dose-dependently attenuated TNF-α-induced intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression, nuclear factor (NF)-kappa B activation in human coronary artery endothelial cells (HCAEC), and the adhesion of monocytes to HCAECs in a CB1- and CB2-dependent manner. It was also shown that the inhibition of the endocannabinoid AEA metabolizing enzyme, the fatty acid amide hydrolase (FAAH) by gene knock-out method, decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice. In our most recent study, we reported activation of the endocannabinoid system by oxLDL in macrophages; the activated endocannabinoid system promotes cellular cholesterol accumulation in macrophages by upregulating CD36 receptor expression and downregulating ATP-binding cassette transporter (ABCA1) expression (4.Jiang L.S. Pu J. Han Z.H. Hu L.H. He B. Role of activated endocannabinoid system in regulation of cellular cholesterol metabolism in macrophages.Cardiovasc. Res. 2009; 81: 805-813Crossref PubMed Scopus (49) Google Scholar). In the present study, we hypothesized that the endocannabinoid system is directly involved in regulating oxLDL-induced inflammation and oxidative stress in macrophages. The protocol involved animals was approved by the Experimental Animal Ethics Committee in Shanghai Jiaotong University School of Medicine. Sprague-Dawley (SD) rats were purchased from the Chinese Academy of Sciences, Shanghai Laboratory Animal Center. All cell culture reagents, including FBS, were purchased from Gibco Life Technologies (USA), and culture materials were purchased from Corning Life Science (USA). MEK1 inhibitor PD98059 and MEK 1/2 signaling pathway inhibitor U0126 were obtained from Merck (USA), and WIN55,212-2 (synthetic nonselective CB1/CB2 agonist), AM251 (selective CB1 antagonist), and AM630 (selective CB2 antagonist) were purchased from Tocris (USA). The RevertaidTM First Strand cDNA Synthesis Kit was from Fermentas International Inc. (Canada), and the SYBR® Premix Ex TaqTM (Perfect Real Time) kit from Takara Inc. (Japan). The mouse and rat TNF-α /TNFSF1A kits were purchased from R and D Systems Inc. (USA). The NE-PER Nuclear and Cytoplasmic Extraction Reagents and the LightShift EMSA kit were obtained from Pierce (USA). The ECL Western Blotting Detection Kit was purchased from Amersham Pharmacia Biotech (Germany). The following antibodies were used: rabbit anti-phospho-p44/42 MAPK (ERK1/2) and rabbit anti total-p44/42 MAPK (ERK1/2) (Cell Signaling Technology; MA); rabbit polyclonal anti-GAPDH antibody (Proteinech Group; USA); and donkey anti-rabbit secondary antibody (Santa Cruz Biotechnology, Santa Cruz, CA). The ROS assay kit was purchased from Sigma (St. Louis, MO), and the BCA Protein Assay Kit was from Beyotime Institute of Biotechnology (China). LDL was isolated from human endotoxin-free heparin plasma by sequential ultracentrifugation (density range, 1.019–1.063 g × ml−1), and dialyzed against PBS at 4°C. LDL protein concentration was determined by a modification of the Lowry method using bovine albumin as the standard. LDL was oxidized with CuSO4 and stored at 4°C as described previously (12.Shen L.H. Zhou L. Wang B.Y. Pu J. Hu L.H. Chai D.J. Wang L. Zeng J.Z. He B. Oxidized low-density lipoprotein induces differentiation of RAW264.7 murine macrophage cell line into dendritic-like cells.Atherosclerosis. 2008; 199: 257-264Abstract PubMed Scopus Google Scholar). macrophages were isolated from rats and with with 2 and as previously described M. The inhibition of of by and peritoneal J. PubMed Scopus Google Scholar). The mouse RAW264.7 macrophage line was in the culture cells were by with and with or U0126 or in The cells were for the following ROS generation in RAW264.7 macrophages and peritoneal macrophages isolated from rats was determined with the ROS assay kit and by the of a with cells were with oxLDL for were with for in the and in PBS for was at and TNF-α levels in the cell culture were determined by mouse and rat kits to the were as were with for the TNF-α was and and of were TNF-α and levels were determined using the SYBR® Premix Ex TaqTM (Perfect Real Time) kit and an CA). The following were used: mouse TNF-α and rat TNF-α and and was to cDNA with the RevertaidTM First cDNA Synthesis was as at for by of for and for expression was determined with the method using as the RAW264.7 macrophages and peritoneal macrophages isolated from rats were in and 2 materials were by at at 4°C for and protein concentration was determined using the BCA Protein Assay for with protein were by and at 4°C. for with in were at 4°C with antibodies for and and with secondary antibodies and by using an ECL Western Blotting Detection of the was with CA). Nuclear and for the assay were described previously expression in in human endothelial cells and in in the of J. PubMed Scopus Google Scholar). The synthetic as NF-kappa B in the assay were and was by the to between were as of the was as oxLDL with or without receptor or signaling pathway ROS was determined in macrophages by using the which is to by of RAW264.7 macrophages to oxLDL for to a increase in ROS with increase in cells of and at of and with WIN55,212-2 attenuated the ROS generation induced by of oxLDL in a the of WIN55,212-2 was by AM251 or AM630 with AM630 a AM251 ROS by oxLDL was also decreased by with PD98059 or of the MEK signaling pathway A was also observed in peritoneal macrophages isolated from rats of oxLDL were to ROS generation in oxLDL of RAW264.7 macrophages, that TNF-α protein levels were dose-dependently in the cell culture the TNF-α secretion induced by of oxLDL was decreased by with WIN55,212-2 a was with a at In cells with the of WIN55,212-2 in TNF-α protein secretion was by AM251 or AM630 with AM630 a AM251 observed in the ROS the TNF-α protein levels by of oxLDL were also attenuated by with PD98059 and U0126 A was observed in rat peritoneal macrophages with oxLDL TNF-α expression the as protein expression, as determined by TNF-α levels with oxLDL in RAW264.7 murine macrophages and rat peritoneal macrophages but the oxLDL-induced increase was attenuated by WIN55,212-2 The of WIN55,212-2 was by AM251 or with AM630 a AM251 oxLDL-induced TNF-α expression was also decreased by PD98059 and U0126 NF-kappa B in RAW264.7 macrophages was determined by The results that with oxLDL NF-kappa B with cells in with WIN55,212-2 in a in NF-kappa B AM251 or AM630 the effects of this was Western was to the role of the MAPK (ERK1/2) pathway in WIN55,212-2 regulation of TNF-α and ROS in murine macrophages A with oxLDL to a of with the in with WIN55,212-2 decreased oxLDL-induced activation The in activation was by AM251 or AM630 with AM630 a A with PD98059 or U0126 to oxLDL-induced There were in this oxLDL-induced TNF-α expression and ROS generation in RAW264.7 mouse macrophages and in rat peritoneal macrophages were considerably by the synthetic cannabinoid WIN55,212-2 TNF-α expression and ROS via the CB2 and linked with the CB1 MAPK and NF-kappa B were by CB1/CB2 receptor signaling, their involvement in the of TNF-α expression and ROS Atherosclerosis is no longer considered simply a lipid metabolism disorder, but a subacute inflammatory condition of the vascular system. The in but is that activation of the acute response in a to a lipid which may play a role in and The of oxLDL to the receptor to endothelial injury and monocyte as as pathological effects (3.Ogura S. Kakino A. Sato Y. Fujita Y. Iwamoto S. Otsui K. Yoshimoto R. Sawamura T. LOX-1: the multifunctional receptor underlying cardiovascular dysfunction.Circ. J. 2009; 73: 1993-1999Crossref PubMed Scopus (90) Google Scholar). in the subintimal oxLDL the receptor pathways and foam cells, which are to cells also produce ROS T. oxidative stress and the of PubMed Scopus Google Scholar), and a of proinflammatory including TNF-α and (12.Shen L.H. Zhou L. Wang B.Y. Pu J. Hu L.H. Chai D.J. Wang L. Zeng J.Z. He B. Oxidized low-density lipoprotein induces differentiation of RAW264.7 murine macrophage cell line into dendritic-like cells.Atherosclerosis. 2008; 199: 257-264Abstract PubMed Scopus Google A. Z. in and 2006; PubMed Scopus Google Scholar), the of and inflammation B. 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In a hepatic I/R injury the AEA and in the and with the of hepatic and the levels of macrophage inflammatory protein and a of to peroxide, or inflammatory stimuli also increases endocannabinoid the selective CB2 cannabinoid receptor protects against I/R by inflammatory cell and and lipid and expression of adhesion molecule in Accordingly, hepatic and inflammation are in mice (6.Bátkai S. Osei-Hyiaman D. Pan H. El-Assal O. Rajesh M. Mukhopadhyay P. Hong F. Harvey-White J. Jafri A. Haskó G. et al.Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury.FASEB J. 2007; 21: 1788-1800Crossref PubMed Scopus (219) Google Scholar). In of the cannabinoid of appear to the of is associated with and secretion by cells as as macrophage into lesions S. C. G. F. C. M. Zimmer A. F. cannabinoid reduces of in PubMed Scopus Google Scholar). These effects of appear to be Filippo et al. (7.Di Filippo C. Rossi F. Rossi S. D'Amico M. Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia- reperfusion injury: involvement of cytokine/chemokines and PMN.J. Leukoc. Biol. 2004; 75: 453-459Crossref PubMed Scopus (111) Google Scholar) demonstrated that with the synthetic nonselective CB1/CB2 receptor WIN55,212-2 the of myocardial in mice from myocardial I/R was by and and levels in the was by the selective CB2 antagonist but was by the selective CB1 antagonist In myocardial in mice with I/R and the was linked with oxidative stress and in the F. S. V. F. G. M. F. S. cannabinoid receptor activation is in a mouse of 2009; PubMed Scopus Google Scholar). as a indicate that effects via the CB2 receptor S. M. P. H. F. to via cannabinoid CB2 receptors in the rat J. 2008; PubMed Scopus Google Scholar). In our study, we demonstrated that the endocannabinoid system is activated by oxLDL in macrophages. In we observed that WIN55,212-2 cellular cholesterol accumulation in macrophages, which was associated with CD36 expression and decreased expression via receptor (4.Jiang L.S. Pu J. Han Z.H. Hu L.H. He B. Role of activated endocannabinoid system in regulation of cellular cholesterol metabolism in macrophages.Cardiovasc. Res. 2009; 81: 805-813Crossref PubMed Scopus (49) Google Scholar). To the that the endocannabinoid system is involved in regulating oxLDL-induced inflammation and oxidative stress, we determined the of WIN55,212-2 oxLDL-induced TNF-α expression and ROS generation in RAW264.7 macrophages and in peritoneal macrophages isolated from We observed that elevated TNF-α and ROS were dose-dependently attenuated by WIN55,212-2. results were with WIN55,212-2 decreased TNF-α in human Hu S. cannabinoid generation of inflammatory by human PubMed Scopus Google Scholar) and lipopolysaccharide TNF-α production in human cells of the cannabinoid receptor the production by human 2004; Google Scholar) in is evidence that WIN55,212-2 reduces ROS in with K. of protein kinase A in cannabinoid receptor protection from oxidative PubMed Scopus Google Scholar) and protects against I/R by inflammation and oxidative stress (6.Bátkai S. Osei-Hyiaman D. Pan H. El-Assal O. Rajesh M. Mukhopadhyay P. Hong F. Harvey-White J. Jafri A. Haskó G. et al.Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury.FASEB J. 2007; 21: 1788-1800Crossref PubMed Scopus (219) Google Filippo C. Rossi F. Rossi S. D'Amico M. Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia- reperfusion injury: involvement of cytokine/chemokines and PMN.J. Leukoc. Biol. 2004; 75: 453-459Crossref PubMed Scopus (111) Google P. Haskó G. and cannabinoid receptors in injury and J. 2008; PubMed Scopus Google F. S. V. F. G. M. F. S. cannabinoid receptor activation is in a mouse of 2009; PubMed Scopus Google S. M. P. H. F. to via cannabinoid CB2 receptors in the rat J. 2008; PubMed Scopus Google Scholar). the endocannabinoid system to play a role in the of by oxLDL-induced inflammation and oxidative stress in macrophages. studies have reported that oxLDL activates MAPK signaling to inflammation and oxidative stress in macrophages via (3.Ogura S. Kakino A. Sato Y. Fujita Y. Iwamoto S. Otsui K. Yoshimoto R. Sawamura T. LOX-1: the multifunctional receptor underlying cardiovascular dysfunction.Circ. J. 2009; 73: 1993-1999Crossref PubMed Scopus (90) Google R. S. S. D. A. of LDL inflammatory molecules in human 2008; PubMed Scopus Google Scholar). We hypothesized that MAPK (ERK1/2) signaling may be involved in the of oxLDL-induced ROS generation and TNF-α expression by We that WIN55,212-2 in RAW264.7 macrophages and in peritoneal macrophages isolated from Further, the MEK PD98059 and U0126 oxLDL-induced TNF-α expression and ROS in macrophages, which the of in oxLDL-induced inflammation and oxidative the MAPK signaling pathway may be involved the WIN55,212-2 regulation of TNF-α expression and ROS Nuclear factor NF-kappa B also in the regulation of inflammatory response, and oxidative stress T. or PubMed Scopus Google in the activation of nuclear factor Biol. Med. PubMed Scopus Google Scholar). In cells, NF-kappa B is activated by a of as inflammatory and oxidative stress in the activation of nuclear factor Biol. Med. PubMed Scopus Google L. R. C. L. regulation of NF-kappa B Biol. Med. PubMed Scopus Google T. G. P. The nuclear factor signaling pathway in of vascular smooth muscle cells in and in human Biol. PubMed Scopus Google Scholar). In the present study, we that WIN55,212-2 oxLDL-induced NF-kappa B with our recent studies that a CB2 proinflammatory expression in and and in monocytes J. M. S. I. J.Z. K.H. M. Zimmer A. is a Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar). induces a from a to a response by the pathway by activation of the receptor J. in a of receptor Biol. 2008; PubMed Google Scholar). studies have the role of the CB2 receptor in the anti-inflammatory and anti-oxidative effects of WIN55,212-2 (6.Bátkai S. Osei-Hyiaman D. Pan H. El-Assal O. Rajesh M. Mukhopadhyay P. Hong F. Harvey-White J. Jafri A. Haskó G. et al.Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury.FASEB J. 2007; 21: 1788-1800Crossref PubMed Scopus (219) Google Filippo C. Rossi F. Rossi S. D'Amico M. Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia- reperfusion injury: involvement of cytokine/chemokines and PMN.J. Leukoc. Biol. 2004; 75: 453-459Crossref PubMed Scopus (111) Google P. Haskó G. and cannabinoid receptors in injury and J. 2008; PubMed Scopus Google F. S. V. F. G. M. F. S. cannabinoid receptor activation is in a mouse of 2009; PubMed Scopus Google S. M. P. H. F. to via cannabinoid CB2 receptors in the rat J. 2008; PubMed Scopus Google Scholar). In the present study, we observed that the selective CB2 receptor antagonist AM630 the effects of WIN55,212-2 oxLDL-induced TNF-α expression, ROS and These results an role for the CB2 receptor in the and of WIN55,212-2. AM251 or AM630 effects the of WIN55,212-2 to NF-kappa B which a CB1/CB2 receptors in the regulation of inflammation and oxidative stress by We demonstrated for the that the cannabinoid WIN55,212-2 protects against oxLDL-induced inflammation and oxidative stress in murine macrophages via the CB2 which that the CB2 receptor be a target for the involvement of receptors and be at this

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