To view the fulltext, please log in
To view the pdf, please log in
Results of the present study demonstrate that activation of the adenylyl cyclase/protein kinase A (PKA) pathway leads to increased levels of insulin-like growth factor I (IGF-I) in cultured embryonic mouse mandibular mesenchymal cells. Treatment of serum-free cultures with 10–8M 8-OH-DPAT (DPAT) or with 10–5M forskolin in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX; 10–5M) increased levels of IGF-I (but not IGF-II), as measured by [125I]protein A immunobinding. In a previous study, we showed that DPAT, forskolin, IBMX and the 5-HT4 receptor agonist SC53116 all increased the synthesis of cyclic adenosine monophosphate (cAMP) in these cultures. Taken together, these results provide evidence that stimulation of the adenylyl cyclase/PKA pathway in embryonic mandibular mesenchymal cells positively regulates IGF-I. This is supported by the ability of the PKA inhibitor Rp-cAMPS to block increases in IGF-I caused by both DPAT and forskolin. Consistent with these results, DPAT and forskolin increased phosphorylation of the cAMP response element binding protein (CREB), which was also blocked by Rp-cAMPS. These results suggest that activation of 5-HT receptors positively coupled to the adenylyl cyclase/PKA pathway may promote transcription of IGF-I through a cAMP response element (CRE) in the IGF-I promoter. This may represent one mechanism whereby 5-HT positively regulates IGF-I expression in developing craniofacial mesenchymal cells.
Copyright / Drug Dosage
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
- Albert PR, Sajedi N, Lemonde S, Ghahremani MH (1999): Constitutive Gi2-dependent activation of adenylyl cyclase type II by the 5-HT1A receptor. J Biol Chem 274:35469–35474.
- Argez MV, Solursh M, Reiter RS (1984): The presence of serotonin in animal sera used in cell culture. Biog Amines 1:223–228.
- Bard JA, Zgombick J, Adham N, Vaysse P, Branchek TA, Weinshank RL (1993): Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase. J Biol Chem 268:23422–23426.
- Birnbaumer L (1992): Receptor-to-effector signaling through G proteins: Roles for βγ dimers as well as α subunits. Cell 71:1069–1072.
- Butkerait P, Zheng Y, Hallak H, Graham TE, Miller HA, Burris KD, Molinoff PB, Manning DR (1995): Expression of the human 5-hydroxytryptamine1A receptor in Sf9 cells. J Biol Chem 270:18691–18699.
- Choi DS, Ward SJ, Messaddeq N, Launay JM, Maroteaux L (1997): 5-HT2B receptor-mediated serotonin morphogenetic functions in mouse cranial neural crest and myocardiac cells. Development 124:1745–1755.
- Copeland KC, Underwood LE, Van Wyk JJ (1980): Induction of immunoreactive somatomedin C human serum by growth hormone: Dose-response relationships and effect on chromatographic profiles. J Clin Endocrinol Metab 50:690–697.
- Cowen DS, Sowers RS, Manning DR (1996): Activation of a mitogen-activated protein kinase (ERK2) by the 5-hydroxytryptamine 1A receptor is sensitive not only to inhibitors of phosphatidylinositol 3-kinase, but to an inhibitor of phosphatidylcholine hydrolysis. J Biol Chem 271:22297–22300.
- Dahmer MK, Hart PM, Perlman RL (1990): Studies on the effect of insulin-like growth factor-I on catecholamine secretion from chromaffin cells. J Neurochem 54:931–936.
- Dahmer MK, Perlman RL (1988): Insulin and insulin-like growth factors stimulate DNA synthesis in PC12 pheochromocytoma cells. Endocrinology 122:2109–2113.
- Edelman GM, Jones FS (1992): Cytotactin: A morphoregulatory molecule and a target for regulation by homeobox gene products. Trends Biochem Sci 17:228–232.
- Fargin A, Raymond JR, Lohse MJ, Kobilka BK, Caron MG, Lefkowitz RJ (1988): The genomic clone G-21 which resembles a β-adrenergic receptor sequence encodes the 5-HT1A receptor. Nature 335:358–360.
- Furlanetto RW, Underwood LE, Van Wyk JJ, D’Ercole AJ (1977): Estimation of somatomedin-C levels in normals and patients with pituitary disease by radioimmunoassay. J Clin Invest 60:648–657.
- Gao B, Chen J, Johnson C, Kunos G (1997): Both the cyclic AMP response element and the activator protein 2 binding site mediate basal and cyclic AMP-induced transcription from the dominant promoter of the rat α1B-adrenergic receptor gene in DDT1MF-2 cells. Mol Pharmocol 52:1019–1026.
- Garcia MA, Campillos M, Marina A, Valdivieso F, Vazquez J (1999): Transcription factor AP-2 activity is modulated by protein kinase A-mediated phosphorylation. FEBS Lett 444:27–31.
- Garnovskaya MN, van Biesen T, Hawe B, Casanas Ramos S, Lefkowitz RJ, Raymond JR (1996): Ras-dependent activation of fibroblast mitogen-activated protein kinase by 5-HT1A receptor via a G protein beta gamma-subunit-initiated pathway. Biochemistry 35:13716–13722.
- Glantschnig H, Varga F, Luegmayr E, Klaushofer K (1998): Characterization of the mouse insulin-like growth factor binding protein 4 gene regulatory region and expression studies. DNA Cell Biol 17:51–60.
- Grant MB, Tarnuzzer RW, Caballero S, Ozeck MJ, Davis MI, Spoerri PE, Feoktistov I, Biaggioni I, Shryock JC, Belardinelli L (1999): Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells. Circ Res 85:699–706.
- Green BN, Jones SB, Streck RD, Wood TL, Rotwein P, Pintar JE (1994): Distinct expression patterns of insulin-like growth factor binding proteins 2 and 5 during fetal and postnatal development. Endocrinology 134:954–962.
- Guillet-Deniau I, Brumol A-F, Girard J (1997): Identification and localization of skeletal muscle serotonin 5-HT2A receptor coupled to the Jak/STAT pathway. J Biol Chem 272:14825–14829.
- Hassell JR, Horigan EA (1982): Chondrogenesis: A model developmental system for measuring teratogenic potential of compounds. Teratog Carcinog Mutagen 2:325–331.
- Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP (1994): International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 46:157–203.
- Hunt SP, Mantyh PW (1984): Radioimmunocytochemistry with [3H]biotin. Brain Res 291:203–217.
- Hwang O, Choi HJ (1995): Induction of gene expression of the catecholamine-synthesizing enzymes by insulin-like growth factor-I. J Neurochem 65:1988–1996.
- Hwang O, Park SY, Kim KS (1997): Protein kinase A coordinately regulates both basal expression and cyclic AMP-mediated induction of three catecholamine-synthesizing enzyme genes. J Neurochem 68:2241–2247.
- Jones JI, Clemmons DR (1995): Insulin-like growth factors and their binding proteins: Biological actions. Endocr Rev 16:3–34.
- Laemmli UK (1970): Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685.
- Lalli E, Sasson-Corsi P (1994): Signal transduction and gene regulation: The nuclear response to cAMP. J Biol Chem 269:17359–17362.
- Lambert HW, Lauder JM (1999): Serotonin receptor agonists that increase cyclic AMP positively regulate IGF-I in mouse mandibular mesenchymal cells. Dev Neurosci 21:105–112.
- Lauder JM (1988): Neurotransmitters as morphogens. Prog Brain Res 73:365–387.
- Lauder JM (1993): Neurotransmitters as growth regulatory signals: Role of receptors and second messengers. Trends Neurosci 16:233–240.
- Lauder JM, Moiseiwitsch JR, Liu J, Wilkie MB (1994): Serotonin in development and pathophysiology; in Lou HC, Greisen G, Larsen JF (eds): Brain Lesions in the Newborn. Copenhagen, Munksgaard, pp 60–72.
- Launay JM, Birraux G, Bondoux D, Callebert J, Choi DS, Loric S, Maroteaux L (1996): Ras involvement in signal transduction by the serotonin 5-HT2B receptor. J Biol Chem 271:3141–3147.
- Levitt P, Harvey JA, Friedman E, Simansky K, Murphy EH (1997): New evidence for neurotransmitter influences on brain development. Trends Neurosci 20:269–274.
- Liu YF, Ghahremani MH, Rasenick MM, Jakobs KH, Albert PR (1999): Stimulation of cAMP synthesis by Gi-coupled receptors upon ablation of Gαι protein expression: Gi subtype specificity of the 5-HT1A receptor. J Biol Chem 274:16444–16450.
- McCarthy TL, Thomas MJ, Centrella M, Rotwein P (1995): Regulation of insulin-like growth factor I transcription by cyclic adenosine 3′,5′-monophosphate (cAMP) in fetal bone cells through an element within exon 1: Protein kinase A-dependent control without a consensus AMP response element. Endocrinology 136:3901–3908.
- Markstein R, Matsumoto M, Kohler C, Togashi H, Yoshioka M, Hoyer D (1999): Pharmacological characterisation of 5-HT receptors positively coupled to adenylyl cyclase in the rat hippocampus. Naunyn Schmiedebergs Arch Pharmacol 359:454–459.
- Moiseiwitsch JR, LauderJM (1995): Serotonin regulates mouse cranial neural crest migration. Proc Natl Acad Sci USA 92:7182–7186.
- Moiseiwitsch JR, Lauder JM (1997): Regulation of gene expression in cultured embryonic mouse mandibular mesenchyme by serotonin antagonists. Anat Embryol 195:71–78.
- Moiseiwitsch JR, Raymond JR, Tamir H, Lauder JM (1998): Serotonin regulates tooth germ morphogenesis and gene expression in mouse mandibular explant cultures. Arch Oral Biol 43:789–800.
- Murphy LJ, Barron DJ (1993): The IGFs and their binding proteins in murine development. Mol Reprod Dev 35:376–381.
- Oki N, Takahashi S-I, Hidaka H, Conti M (2000): Short term feedback of cAMP in FRTL-5 thyroid cells. J Biol Chem 275:10831–10837.
- Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang J-M, Schwartz J-C (1993): Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation. Proc Natl Acad Sci USA 90:8547–8551.
- Sanders-Bush E, Canton H (1995): Serotonin receptors: Signal transduction pathways; in Bloom FE, Kupfer DJ (eds): Psychopharmacology: The Fourth Generation of Progress. New York, Raven Press, pp 60–72.
- Shen Y, Monsma FJ, Metcalf MA, Jose PA, Hamblin MW, Sibley DR (1993): Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype. J Biol Chem 268:18200–18204.
- Shenker A, Maayani S, Weinstein H, Green JP (1983): Enhanced serotonin-stimulated adenylate cyclase activity in membranes from adult guinea pig hippocampus. Life Sci 32:2335–2342.
- Shuey DL, Sadler TW, Lauder JM (1992): Serotonin as a regulator of craniofacial morphogenesis: Site specific malformations following exposure to serotonin uptake inhibitors. Teratology 46:367–378.
- Shuey DL, Sadler TW, Tamir H, Lauder JM (1993): Serotonin and morphogenesis: Transient expression of serotonin uptake and binding protein during craniofacial morphogenesis in the mouse. Anat Embryol 187:75–85.
- Singh LP, Crook ED (1998): IGF-I-induced increase in matrix protein synthesis in rat mesangial cells is associated with CREB phosphorylation and a wortmannin-sensitive pathway. Diabetes 47:A125.
- Thomas MJ, Umayahara Y, Shu H, Centrella M, Rotwein P, McCarthy TL (1996): Identification of the cAMP response element that controls transcriptional activation of the insulin-like growth factor-I gene by prostaglandin E2 in osteoblasts. J Biol Chem 271:21835–21841.
- Vanhoenacker P, Haegeman G, Leysen JE (2000): 5-HT7 receptors: Current knowledge and future prospects. Trends Pharmocol Sci 21:70–77.
- Weiss ER, Maness P, Lauder JM (1998): Why do neurotransmitters act like growth factors? Perspect Dev Neurobiol 5:323–335.
- Wood TL (1995): Gene-targeting and transgenic approaches to IGF and IGF binding protein function. Am J Physiol (Endocrinol Metab 32) 269:E613–622.
- Wood TL, Brown AL, Rechler MM, Pintar JE (1990): The expression pattern of an insulin-like growth factor (IGF)-binding protein gene is distinct from IGF-II in the midgestational rat embryo. Mol Endocrinol 4:1257–1263.
- Wood TL, Rogier L, Streck RD, Carro J, Green B, Grewal A, Pintar JE (1993): Targeted disruption of the IGFBP-2 gene. Growth Regul 3: 5–8.
- Yavarone MS, Shuey DL, Sadler TW, Lauder JM (1993): Serotonin uptake in the ectoplacental cone and placenta of the mouse. Placenta 14:149–161.