P2Y2 Nucleotide Receptor-Mediated Responses in Brain Cells

Molecular Neurobiology - Tập 41 - Trang 356-366 - 2010
Troy S. Peterson1, Jean M. Camden1, Yanfang Wang1, Cheikh I. Seye2, W. G. Wood3, Grace Y. Sun1, Laurie Erb1, Michael J. Petris1, Gary A. Weisman1
1Department of Biochemistry, Bond Life Sciences Center, University of Missouri, Columbia, USA
2Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, USA
3Department of Pharmacology, University of Minnesota School of Medicine and Geriatric Research, Education and Clinical Center, Minneapolis, USA

Tóm tắt

Acute inflammation is important for tissue repair; however, chronic inflammation contributes to neurodegeneration in Alzheimer's disease (AD) and occurs when glial cells undergo prolonged activation. In the brain, stress or damage causes the release of nucleotides and activation of the Gq protein-coupled P2Y2 nucleotide receptor subtype (P2Y2R) leading to pro-inflammatory responses that can protect neurons from injury, including the stimulation and recruitment of glial cells. P2Y2R activation induces the phosphorylation of the epidermal growth factor receptor (EGFR), a response dependent upon the presence of a SH3 binding domain in the intracellular C terminus of the P2Y2R that promotes Src binding and transactivation of EGFR, a pathway that regulates the proliferation of cortical astrocytes. Other studies indicate that P2Y2R activation increases astrocyte migration. P2Y2R activation by UTP increases the expression in astrocytes of αVβ3/5 integrins that bind directly to the P2Y2R via an Arg-Gly-Asp (RGD) motif in the first extracellular loop of the P2Y2R, an interaction required for Go and G12 protein-dependent astrocyte migration. In rat primary cortical neurons (rPCNs) P2Y2R expression is increased by stimulation with interleukin-1β (IL-1β), a pro-inflammatory cytokine whose levels are elevated in AD, in part due to nucleotide-stimulated release from glial cells. Other results indicate that oligomeric β-amyloid peptide (Aβ1-42), a contributor to AD, increases nucleotide release from astrocytes, which would serve to activate upregulated P2Y2Rs in neurons. Data with rPCNs suggest that P2Y2R upregulation by IL-1β and subsequent activation by UTP are neuroprotective, since this increases the non-amyloidogenic cleavage of amyloid precursor protein. Furthermore, activation of IL-1β-upregulated P2Y2Rs in rPCNs increases the phosphorylation of cofilin, a cytoskeletal protein that stabilizes neurite outgrowths. Thus, activation of pro-inflammatory P2Y2Rs in glial cells can promote neuroprotective responses, suggesting that P2Y2Rs represent a novel pharmacological target in neurodegenerative and other pro-inflammatory diseases.

Tài liệu tham khảo

Lee RK, Knapp S, Wurtman RJ (1999) Prostaglandin E2 stimulates amyloid precursor protein gene expression: inhibition by immunosuppressants. J Neurosci 19:940–947 Arlt S, Beisiegel U, Kontush A (2002) Lipid peroxidation in neurodegeneration: new insights into Alzheimer's disease. Curr Opin Lipidol 13:289–294 Butterfield D, Castegna A, Pocernich C, Drake J, Scapagnini G, Calabrese V (2002) Nutritional approaches to combat oxidative stress in Alzheimer's disease. J Nutr Biochem 13:444–461 Mattson MP (2002) Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer's disease. J Neurovirol 8:539–550 Montine TJ, Neely MD, Quinn JF, Beal MF, Markesbery WR, Roberts LJ, Morrow JD (2002) Lipid peroxidation in aging brain and Alzheimer's disease. Free Radic Biol Med 33:620–626 Perry G, Cash AD, Smith MA (2002) Alzheimer disease and oxidative stress. J Biomed Biotechnol 2:120–123 Liu Q, Raina AK, Smith MA, Sayre LM, Perry G (2003) Hydroxynonenal, toxic carbonyls, and Alzheimer disease. Mol Aspects Med 24:305–313 Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer's disease: the two-hit hypothesis. Lancet Neurol 3:219–226 Zhu X, Raina AK, Lee HG, Casadesus G, Smith MA, Perry G (2004) Oxidative stress signalling in Alzheimer's disease. Brain Res 1000:32–39 Butterfield DA (2002) Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer's disease brain. A review. Free Radic Res 36:1307–1313 Butterfield DA, Boyd-Kimball D (2004) Amyloid beta-peptide(1-42) contributes to the oxidative stress and neurodegeneration found in Alzheimer disease brain. Brain Pathol 14:426–432 Misonou H, Morishima-Kawashima M, Ihara Y (2000) Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells. Biochem 39:6951–6959 Keil U, Bonert A, Marques CA, Scherping I, Weyermann J, Strosznajder JB, Muller-Spahn F, Haass C, Czech C, Pradier L, Muller WE, Eckert A (2004) Amyloid-beta induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem 279:50310–50320 Hu J, Akama KT, Krafft GA, Chromy BA, Van Eldik LJ (1998) Amyloid-beta peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release. Brain Res 785:195–206 Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nat Cell Biol 6:1054–1061 Kim SH, Smith CJ, Van Eldik LJ (2004) Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1 beta production. Neurobiol Aging 25:431–439 Xie Z, Smith CJ, Van Eldik LJ (2004) Activated glia induce neuron death via MAP kinase signaling pathways involving JNK and p38. Glia 45:170–179 Mrak RE, Griffin WS (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26:349–354 O'Callaghan JP, Jensen KF (1992) Enhanced expression of glial fibrillary acidic protein and the cupric silver degeneration reaction can be used as sensitive and early indicators of neurotoxicity. Neurotoxicol 13:113–122 Eddleston M, Mucke L (1993) Molecular profile of reactive astrocytes-implications for their role in neurologic disease. Neurosci 54:15–36 Menet V, Prieto M, Privat A, Gimenez y Ribotta M (2003) Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proc Natl Acad Sci USA 100:8999–9004 Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577 Norton WT, Aquino DA, Hozumi I, Chiu FC, Brosnan CF (1992) Quantitative aspects of reactive gliosis: a review. Neurochem Res 17:877–885 Rutka JT, Murakami M, Dirks PB, Hubbard SL, Becker LE, Fukuyama K, Jung S, Tsugu A, Matsuzawa K (1997) Role of glial filaments in cells and tumors of glial origin: a review. J Neurosurg 87:420–430 Monsonego A, Weiner HL (2003) Immunotherapeutic approaches to Alzheimer's disease. Science 302:834–838 Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27:2866–2875 Gahtan E, Overmier JB (1999) Inflammatory pathogenesis in Alzheimer's disease: biological mechanisms and cognitive sequeli. Neurosci Biobehav Rev 23:615–633 McGraw J, Hiebert GW, Steeves JD (2001) Modulating astrogliosis after neurotrauma. J Neurosci Res 63:109–115 Chan-Ling T, Stone J (1991) Factors determining the migration of astrocytes into the developing retina: migration does not depend on intact axons or patent vessels. J Comp Neurol 303:375–386 Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC, Wegiel J (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease. Neurobiol Aging 25:663–674 Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G (2003) Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci 23:7504–7509 Miller WJ, Leventhal I, Scarsella D, Haydon PG, Janmey P, Meaney DF (2009) Mechanically induced reactive gliosis causes ATP-mediated alterations in astrocyte stiffness. J Neurotrauma 5:789–797 Franke H, Krugel U, Illes P (1999) P2 receptor-mediated proliferative effects on astrocytes in vivo. Glia 28:190–200 Weisman GA, Wang M, Kong Q, Chorna NE, Neary JT, Sun GY, González FA, Seye CI, Erb L (2005) Molecular determinants of P2Y2 nucleotide receptor function: implications for proliferative and inflammatory pathways in astrocytes. Mol Neurobiol 31:169–183 Zimmermann H, Braun N (1996) Extracellular metabolism of nucleotides in the nervous system. J Auton Pharmacol 16:397–400 Franke H, Illes P (2006) Involvement of P2 receptors in the growth and survival of neurons in the CNS. Review. Pharmacol Ther 109:297–324 Gendron FP, Newbold NL, Vivas-Mejia PE, Wang M, Neary JT, Sun GW, Gonzalez FA, Weisman GA (2003) Signal transduction pathways for P2Y2 and P2X7 nucleotide receptors that mediate neuroinflammatory responses in astrocytes and microglial cells. Biomed Res 14:47–61 Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N, Zinkernagel A, Nizet V, Insel PA, Junger WG (2006) ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314:1792–1795 Kong Q, Peterson TS, Baker O, Stanley E, Camden J, Seye CI, Erb L, Simonyi A, Wood WG, Sun GY, Weisman GA (2009) Interleukin-1β enhances nucleotide-induced and α -secretase-dependent amyloid precursor protein processing in rat primary cortical neurons via up-regulation of the P2Y2 receptor. J Neurochem 109:1300–1310 Burnstock G (1972) Purinergic nerves. Pharmacol Rev 24:509–581 Burnstock G, Campbell G, Satchell D, Smythe A (1970) Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut. Br J Pharmacol 40:668–688 Burnstock G, Wood JN (1996) Purinergic receptors: their role in nociception and primary afferent neurotransmission. Curr Opin Neurobiol 6:526–532 Neary JT, Rathbone MP, Cattabeni F, Abbracchio MP, Burnstock G (1996) Trophic actions of extracellular nucleotides and nucleosides on glial and neuronal cells. Trends Neurosci 19:13–18 Vitolo OV, Ciotti MT, Galli C, Borsello T, Calissano P (1998) Adenosine and ADP prevent apoptosis in cultured rat cerebellar granule cells. Brain Res 809:297–301 Ostrom RS, Gregorian C, Drenan RM, Gabot K, Rana BK, Insel PA (2001) Key role for constitutive cyclooxygenase-2 of MDCK cells in basal signaling and response to released ATP. Am J Physiol Cell Physiol 281:C524–C531 Ahmed SM, Rzigalinski BA, Willoughby KA, Sitterding HA, Ellis EF (2000) Stretch-induced injury alters mitochondrial membrane potential and cellular ATP in cultured astrocytes and neurons. J Neurochem 74:1951–1960 Ciccarelli R, Di Iorio P, Giuliani P, D'Alimonte I, Ballerini P, Caciagli F, Rathbone MP (1999) Rat cultured astrocytes release guanine based purines in basal conditions and after hypoxia/hypoglycemia. Glia 25:93–98 Bergfeld GR, Forrester T (1992) Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. Cardiovasc Res 26:40–47 Bodin P, Burnstock G (2001) Purinergic signalling: ATP release. Neurochem Res 26:959–969 Pedersen SF, Nilius B, Lambert IH, Hoffmann EK (1999) Mechanical stress induces release of ATP from Ehrlich ascites tumor cells. Biochim Biophys Acta 1416:271–284 Sak K, Webb TE (2002) A retrospective of recombinant P2Y receptor subtypes and their pharmacology. Arch Biochem Biophys 397:131–136 Burnstock G (2000) P2X receptors in sensory neurones. Br J Anaesth 84:476–488 Ciccarelli R, Ballerini P, Sabatino G, Rathbone MP, D'Onofrio M, Caciagli F, Di Iorio P (2001) Involvement of astrocytes in purine mediated reparative processes in the brain. Int J Dev Neurosci 19:395–414 Weisman GA, Garrad RC, Erb LJ, Santos-Berrios C, Gonzalez FA (1999) P2Y receptors in the nervous system: molecular studies of a P2Y2 receptor subtype from NG108-15 neuroblastoma x glioma hybrid cells. Prog Brain Res 120:33–43 Lustig KD, Erb L, Landis DM, Hicks-Taylor CS, Zhang X, Sportiello MG, Weisman GA (1992) Mechanisms by which extracellular ATP and UTP stimulate the release of prostacyclin from bovine pulmonary artery endothelial cells. Biochim Biophys Acta 1134:61–72 Liao Z, Seye CI, Weisman GA, Erb L (2007) The P2Y2 nucleotide receptor requires interaction with αv integrins to access and activate G12. J Cell Sci 120:1654–1662 Bagchi S, Liao Z, Gonzalez FA, Chorna NE, Seye CI, Weisman GA, Erb L (2005) The P2Y2 nucleotide receptor interacts with αv integrins to activate Go and induce cell migration. J Biol Chem 280:39050–39057 Liu J, Liao Z, Camden J, Griffin KD, Garrad RC, Santiago-Perez LI, Gonzalez FA, Seye CI, Weisman GA, Erb L (2004) SH3 binding sites in the P2Y2 nucleotide receptor interact with Src and regulate activities of Src, Pyk2, and growth factor receptors. J Biol Chem 279:8212–8218 Soltoff SP (1998) Related adhesion focal tyrosine kinase and the epidermal growth factor receptor mediate the stimulation of mitogen-activated protein kinase by the G-protein-coupled P2Y2 receptor. Phorbol ester or [Ca2+]i elevation can substitute for receptor activation. J Biol Chem 273:23110–23117 Soltoff SP, Avraham H, Avraham S, Cantley LC (1998) Activation of P2Y2 receptors by UTP and ATP stimulates mitogen-activated kinase activity through a pathway that involves related adhesion focal tyrosine kinase and protein kinase C. J Biol Chem 273:2653–2660 Washburn KB, Neary JT (2006) P2 purinergic receptors signal to STAT3 in astrocytes: difference in STAT3 responses to P2Y and P2X receptor activation. Neuroscience 142:411–423 Seye CI, Yu N, Jain R, Kong Q, Minor T, Newton J, Erb L, Gonzalez FA, Weisman GA (2003) The P2Y2 nucleotide receptor mediates UTP-induced vascular cell adhesion molecule-1 expression in coronary artery endothelial cells. J Biol Chem 278:24,960–24,965 Baker OJ, Camden JM, Rome DE, Seye CI, Weisman GA (2007) P2Y2 nucleotide receptor activation up-regulates vascular cell adhesion molecule-1 [corrected] expression and enhances lymphocyte adherence to a human submandibular gland cell line. Mol Immunol 45:65–75 Burgos M, Neary JT, González FA (2007) P2Y2 nucleotide receptors inhibit trauma-induced death of astrocytic cells. J Neurochem 103:1785–1800 Wagner B, Natarajan A, Grünaug S, Kroismayr R, Wagner EF, Sibilia M (2006) Neuronal survival depends on EGFR signaling in cortical but not midbrain astrocytes. EMBO J 25:752–762 Yu N, Erb L, Shivaji R, Weisman GA, Seye CI (2008) Binding of the P2Y2 nucleotide receptor to filamin A regulates migration of vascular smooth muscle cells. Circ Res 102:581–588 Seye CI, Kong Q, Erb L, Garrad RC, Krugh B, Wang M, Turner JT, Sturek M, González FA, Weisman GA (2002) Functional P2Y2 nucleotide receptors mediate uridine 5′-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries. Circ 106:2720–2726 Pillois X, Chaulet H, Belloc I, Dupuch F, Desgranges C, Gadeau AP (2002) Nucleotide receptors involved in UTP-induced rat arterial smooth muscle cell migration. Circ Res 90:678–681 Kunapuli SP, Daniel JL (1998) P2 receptor subtypes in the cardiovascular system. Biochem J 336:513–523 Kim KC, Park HR, Shin CY, Akiyama T, Ko KH (1996) Nucleotide-induced mucin release from primary hamster tracheal surface epithelial cells involves the P2u purinoceptor. Eur Respir J 9:542–548 Berti-Mattera LN, Wilkins PL, Madhun Z, Suchovsky D (1996) P2-purigenic receptors regulate phospholipase C and adenylate cyclase activities in immortalized Schwann cells. Biochem J 314:555–561 Ho C, Hicks J, Salter MW (1995) A novel P2-purinoceptor expressed by a subpopulation of astrocytes from the dorsal spinal cord of the rat. Br J Pharmacol 116:2909–2918 Kirischuk S, Scherer J, Kettenmann H, Verkhratsky A (1995) Activation of P2-purinoreceptors triggered Ca2+ release from InsP3- sensitive internal stores in mammalian oligodendrocytes. J Physiol 483:41–57 Boucsein C, Zacharias R, Färber K, Pavlovic S, Hanisch UK, Kettenmann H (2003) Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur J Neurosci 11:2267–2276 Koshiba M, Apasov S, Sverdlov V, Chen P, Erb L, Turner JT, Weisman GA, Sitkovsky MV (1997) Transient up-regulation of P2Y2 nucleotide receptor mRNA expression is an immediate early gene response in activated thymocytes. Proc Natl Acad Sci USA 94:831–836 Hou M, Moller S, Edvinsson L, Erlinge D (2000) Cytokines induce upregulation of vascular P2Y2 receptors and increased mitogenic responses to UTP and ATP. Arterioscler Thromb Vasc Biol 20:2064–2069 Schrader AM, Camden JM, Weisman GA (2005) P2Y2 nucleotide receptor up-regulation in submandibular gland cells from the NOD.B10 mouse model of Sjögren's syndrome. Arch Oral Biol 50:533–540 Ventura MA, Thomopoulos P (1995) ADP and ATP activate distinct signaling pathways in human promonocytic U-937 cells differentiated with 1, 25-dihydroxy-vitamin D3. Mol Pharmacol 47:104–114 Parker AL, Likar LL, Dawicki DD, Rounds S (1996) Mechanism of ATP-induced leukocyte adherence to cultured pulmonary artery endothelial cells. Am J Physiol 270:L695–L703 Weisman GA, Garrad RC, Erb LJ, Otero M, Gonzalez FA, Clarke LL (1998) Structure and function of P2Y2 nucleotide receptors in cystic fibrosis (CF) epithelium. Adv Exp Med Biol 431:417–424 Denlinger LC, Fisette PL, Garis KA, Kwon G, Vazquez-Torres A, Simon AD, Nguyen B, Proctor RA, Bertics PJ, Corbett JA (1996) Regulation of inducible nitric oxide synthase expression by macrophage purinoreceptors and calcium. J Biol Chem 271:337–342 Grimm I, Messemer N, Stanke M, Gachet C, Zimmermann H (2009) Coordinate pathways for nucleotide and EGF signaling in cultured adult neural progenitor cells. J Cell Sci 122:2524–2533 Chaulet H, Desgranges C, Renault MA, Dupuch F, Ezan G, Peiretti F, Loirand G, Pacaud P, Gadeau AP (2001) Extracellular nucleotides induce arterial smooth muscle cell migration via osteopontin. Circ Res 89:772–778 Goepfert C, Sundberg C, Sevigny J, Enjyoji K, Hoshi T, Csizmadia E, Robson S (2001) Disordered cellular migration and angiogenesis in cd39-null mice. Circ 104:3109–3115 Honda S, Sasaki Y, Ohsawa K, Imai Y, Nakamura Y, Inoue K, Kohsaka S (2001) Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J Neurosci 21:1975–1982 Ballerini P, Di Iorio P, Caciagli F, Rathbone MP, Jiang S, Nargi E, Buccella S, Giuliani P, D'Alimonte I, Fischione G, Masciulli A, Romano S, Ciccarelli R (2006) P2Y2 receptor up-regulation induced by guanosine or UTP in rat brain cultured astrocytes. Int J Immunopathol Pharmacol 19:293–308 Hou M, Moller S, Edvinsson L, Erlinge D (1999) MAPKK-dependent growth factor induced upregulation of P2Y2 receptors in vascular smooth muscle cells. Biochem Biophys Res Commun 258:648–652 Morigiwa K, Fukuda Y, Yamashita M (2000) Neurotransmitter ATP and cytokine release. Nippon Yakurigaku Zasshi Review 115:185–192, Japanese Camden JM, Schrader AM, Camden RE, González FA, Erb L, Seye CI, Weisman GA (2005) P2Y2 nucleotide receptors enhance α-secretase-dependent amyloid precursor protein processing. J Biol Chem 280:18696–18702 Colangelo J, Schurr MJ, Ball RP, Pelaez RP, Bazan NG, Lukiw WJ (2002) Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 70:462–473 Bianco F, Pravettoni E, Colombo A, Schenk U, Möller T, Matteoli M, Verderio C (2005) Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J Immunol 174:7268–7277 Degagné E, Grbic DM, Dupuis AA, Lavoie EG, Langlois C, Jain N, Weisman GA, Sévigny J, Gendron FP (2009) P2Y2 receptor transcription is increased by NF-κB and stimulates cyclooxygenase-2 expression and PGE2 release by intestinal epithelial cells. J Immunol 183:4521–4529 Rex CS, Chen LY, Sharma A, Liu J, Babayan AH, Gall CM, Lynch G (2009) Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J Cell Biol 186:85–97 Okamura K, Tanaka H, Yagita Y, Saeki Y, Taguchi A, Hiraoka Y, Zeng LH, Colman DR, Miki N (2004) Cadherin activity is required for activity-induced spine remodeling. J Cell Biol 167:961–972 Arthur DB, Akassoglou K, Insel PA (2005) P2Y2 receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation. Proc Natl Acad Sci USA 102:19138–19143 Anderson JP, Esch FS, Keim PS, Sambamurti K, Lieberburg I, Robakis NK (1991) Exact cleavage site of Alzheimer precursor protein in neuronal PC12 cells. Neurosci Lett 128:126–128 Roher AE, Chaney MO, Kuo YM, Webster SD, Stine WB, Haverkamp LJ, Woods AS, Cotter RJ, Tuohy JM, Krafft GA, Bonnell BS, Emmerling MR (1996) Morphology and toxicity of Abeta-(1-42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer's disease. J Biol Chem 271:20631–20635 Mattson MP (1997) Cellular actions of β-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 77:1081–1132 Selkoe DJ (1994) Cell biology of the amyloid β-protein precursor and the mechanism of Alzheimer's disease. Annu Rev Cell Biol 10:373–403 Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81:741–766 Mills J, Reiner PB (1999) Regulation of amyloid precursor protein cleavage. J Neurochem 72:443–460 Weidemann A, Konig G, Bunke D, Fischer P, Salbaum JM, Masters CL, Beyreuther K (1989) Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell 57:115–126 Oltersdorf T, Ward PJ, Henriksson T, Beattie EC, Neve R, Lieberburg I, Fritz LC (1990) The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway. J Biol Chem 265:4492–4497 Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ (1992) Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357:500–503 Wallace WC, Akar CA, Lyons WE (1997) Amyloid precursor protein potentiates the neurotrophic activity of NGF. Brain Res Mol Brain Res 52:201–212 Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I, Rydel RE (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein. Neuron 10:243–254 Bowes MP, Masliah E, Otero DA, Zivin JA, Saitoh T (1994) Reduction of neurological damage by a peptide segment of the amyloid β/A4 protein precursor in a rabbit spinal cord ischemia model. Exp Neurol 129:112–119 Smith-Swintosky VL, Pettigrew LC, Craddock SD, Culwell AR, Rydel RE, Mattson MP (1994) Secreted forms of β-amyloid precursor protein protect against ischemic brain injury. J Neurochem 63:781–784 Barger SW, Van Eldik LJ, Mattson MP (1995) S100β protects hippocampal neurons from damage induced by glucose deprivation. Brain Res 677:167–170 Nitsch RM, Slack BE, Farber SA, Schulz JG, Deng M, Kim C, Borghesani PR, Korver W, Wurtman RJ, Growdon JH (1994) Regulation of proteolytic processing of the amyloid β-protein precursor of Alzheimer's disease in transfected cell lines and in brain slices. J Neural Transmiss Suppl 44:21–27 Nitsch RM, Wurtman RJ, Growdon JH (1995) Regulation of proteolytic processing of the amyloid β-protein precursor by first messengers. A novel potential approach for the treatment of Alzheimer's disease. Arzneimittel-Forschung 45:435–438 Checler F (1995) Processing of the β-amyloid precursor protein and its regulation in Alzheimer's disease. J Neurochem 65:1431–1444 Nitsch RM, Slack BE, Wurtman RJ, Growdon JH (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258:304–307 Nitsch RM, Slack BE, Farber SA, Borghesani PR, Schulz JG, Kim C, Felder CC, Growdon JH, Wurtman RJ (1993) Receptor-coupled amyloid precursor protein processing. Ann NY Acad Sci 695:122–127 Nitsch RM, Deng M, Growdon JH, Wurtman RJ (1996) Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. J Biol Chem 271:4188–4194 Nitsch RM, Deng A, Wurtman RJ, Growdon JH (1997) Metabotropic glutamate receptor subtype mGluR1α stimulates the secretion of the amyloid β-protein precursor ectodomain. J Neurochem 69:704–712 Davis-Salinas J, Saporito-Irwin SM, Donovan FM, Cunningham DD, Van Nostrand WE (1994) Thrombin receptor activation induces secretion and nonamyloidogenic processing of amyloid β-protein precursor. J Biol Chem 269:22623–22627 Lee RK, Wurtman RJ, Cox AJ, Nitsch RM (1995) Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors. Proc Natl Acad Sci USA 92:8083–8087 Hung AY, Haass C, Nitsch RM, Qiu WQ, Citron M, Wurtman RJ, Growdon JH, Selkoe DJ (1993) Activation of protein kinase C inhibits cellular production of the amyloid β-protein. J Biol Chem 268:22959–22962 Buxbaum JD, Koo EH, Greengard P (1993) Protein phosphorylation inhibits production of Alzheimer amyloid β/A4 peptide. Proc Natl Acad Sci USA 90:9195–9198 Wolf BA, Wertkin AM, Jolly YC, Yasuda RP, Wolfe BB, Konrad RJ, Manning D, Ravi S, Williamson JR, Lee VM (1995) Alzheimer's disease amyloid precursor protein secretion and amyloid β-protein production in human neuronal NT-2 cells. J Biol Chem 270:4916–4922 Rooke J, Pan D, Xu T, Rubin GM (1996) KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis. Science 273:1227–1231 Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385:729–733 Black RA, Kronheim SR, Sleath PR (1989) Activation of interleukin-1β by a co-induced protease. FEBS Lett 247:386–390 Takemura M, Mishima T, Wang Y, Kasahara J, Fukunaga K, Ohashi K, Mizuno K (2009) Ca2+/calmodulin-dependent protein kinase IV-mediated LIM kinase activation is critical for calcium signal-induced neurite outgrowth. J Biol Chem 284:28554–28562 Bramham CR, Worley PF, Moore MJ, Guzowski JF (2008) The immediate early gene arc/arg3.1: regulation, mechanisms, and function. Review. J Neurosci 28:11760–11767 Cunningham CC, Gorlin JB, Kwiatkowski DJ, Hartwig JH, Janmey PA, Byers HR, Stossel TP (1992) Actin-binding protein requirement for cortical stability and efficient locomotion. Science 255:325–327