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Caveolin regulation of neuronal intracellular signaling

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Abstract

Caveolin proteins physically interact with and compartmentalize membrane-localized signaling proteins to facilitate high-fidelity intracellular signaling. Though primarily studied outside the nervous system, recent investigations have revealed that caveolin proteins are key modulators of a variety of neuronal intracellular signaling pathways. Through both protein aggregation and segregation, caveolin proteins can exert positive and negative influences on intracellular signaling. This review will detail recent findings regarding caveolin function in the brain.

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References

  1. Singer SJ, Nicolson GL (1972) The fluid mosaic model of the structure of cell membranes. Science 175:720–731

    Article  CAS  PubMed  Google Scholar 

  2. Allen JA, Halverson-Tamboli RA, Rasenick MM (2007) Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci 8:128–140

    Article  CAS  PubMed  Google Scholar 

  3. Yamada E (1955) The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol 1:445–458

    Article  CAS  PubMed  Google Scholar 

  4. Patel HH, Murray F, Insel PA (2008) Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol 48:359–391

    Article  CAS  PubMed  Google Scholar 

  5. Glenney JR Jr (1992) The sequence of human caveolin reveals identity with VIP21, a component of transport vesicles. FEBS Lett 314:45–48

    Article  CAS  PubMed  Google Scholar 

  6. Scherer PE, Okamoto T, Chun M, Nishimoto I, Lodish HF, Lisanti MP (1996) Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. Proc Natl Acad Sci USA 93:131–135

    Article  CAS  PubMed  Google Scholar 

  7. Tang Z, Scherer PE, Okamoto T, Song K, Chu C, Kohtz DS, Nishimoto I, Lodish HF, Lisanti MP (1996) Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle. J Biol Chem 271:2255–2261

    Article  CAS  PubMed  Google Scholar 

  8. Galbiati F, Volonte D, Gil O, Zanazzi G, Salzer JL, Sargiacomo M, Scherer PE, Engelman JA, Schlegel A, Parenti M, Okamoto T, Lisanti MP (1998) Expression of caveolin-1 and -2 in differentiating PC12 cells and dorsal root ganglion neurons: caveolin-2 is up-regulated in response to cell injury. Proc Natl Acad Sci USA 95:10257–10262

    Article  CAS  PubMed  Google Scholar 

  9. Ikezu T, Ueda H, Trapp BD, Nishiyama K, Sha JF, Volonte D, Galbiati F, Byrd AL, Bassell G, Serizawa H, Lane WS, Lisanti MP, Okamoto T (1998) Affinity-purification and characterization of caveolins from the brain: differential expression of caveolin-1, -2, and -3 in brain endothelial and astroglial cell types. Brain Res 804:177–192

    Article  CAS  PubMed  Google Scholar 

  10. Lisanti MP, Scherer PE, Vidugiriene J, Tang Z, Hermanowski-Vosatka A, Tu YH, Cook RF, Sargiacomo M (1994) Characterization of caveolin-rich membrane domains isolated from an endothelial-rich source: implications for human disease. J Cell Biol 126:111–126

    Article  CAS  PubMed  Google Scholar 

  11. Vogel U, Sandvig K, van Deurs B (1998) Expression of caveolin-1 and polarized formation of invaginated caveolae in Caco-2 and MDCK II cells. J Cell Sci 111(Pt 6):825–832

    CAS  PubMed  Google Scholar 

  12. Song KS, Scherer PE, Tang Z, Okamoto T, Li S, Chafel M, Chu C, Kohtz DS, Lisanti MP (1996) Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins. J Biol Chem 271:15160–15165

    Article  CAS  PubMed  Google Scholar 

  13. Way M, Parton RG (1995) M-caveolin, a muscle-specific caveolin-related protein. FEBS Lett 376:108–112

    Article  CAS  PubMed  Google Scholar 

  14. Chang WJ, Ying YS, Rothberg KG, Hooper NM, Turner AJ, Gambliel HA, De Gunzburg J, Mumby SM, Gilman AG, Anderson RG (1994) Purification and characterization of smooth muscle cell caveolae. J Cell Biol 126:127–138

    Article  CAS  PubMed  Google Scholar 

  15. Galbiati F, Engelman JA, Volonte D, Zhang XL, Minetti C, Li M, Hou H Jr, Kneitz B, Edelmann W, Lisanti MP (2001) Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and t-tubule abnormalities. J Biol Chem 276:21425–21433

    Article  CAS  PubMed  Google Scholar 

  16. Razani B, Combs TP, Wang XB, Frank PG, Park DS, Russell RG, Li M, Tang B, Jelicks LA, Scherer PE, Lisanti MP (2002) Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J Biol Chem 277:8635–8647

    Article  CAS  PubMed  Google Scholar 

  17. Scherer PE, Lewis RY, Volonte D, Engelman JA, Galbiati F, Couet J, Kohtz DS, van Donselaar E, Peters P, Lisanti MP (1997) Cell-type and tissue-specific expression of caveolin-2. Caveolins 1 and 2 co-localize and form a stable hetero-oligomeric complex in vivo. J Biol Chem 272:29337–29346

    Article  CAS  PubMed  Google Scholar 

  18. Cameron PL, Ruffin JW, Bollag R, Rasmussen H, Cameron RS (1997) Identification of caveolin and caveolin-related proteins in the brain. J Neurosci 17:9520–9535

    CAS  PubMed  Google Scholar 

  19. Zschocke J, Manthey D, Bayatti N, van der Burg B, Goodenough S, Behl C (2002) Estrogen receptor alpha-mediated silencing of caveolin gene expression in neuronal cells. J Biol Chem 277:38772–38780

    Article  CAS  PubMed  Google Scholar 

  20. Boulware MI, Kordasiewicz H, Mermelstein PG (2007) Caveolin proteins are essential for distinct effects of membrane estrogen receptors in neurons. J Neurosci 27:9941–9950

    Article  CAS  PubMed  Google Scholar 

  21. D’Orlando C, Guzzi F, Gravati M, Biella G, Toselli M, Meneveri R, Barisani D, Parenti M (2008) Retinoic acid- and phorbol ester-induced neuronal differentiation down-regulates caveolin expression in GnRH neurons. J Neurochem 104:1577–1587

    Article  PubMed  Google Scholar 

  22. Head BP, Insel PA (2007) Do caveolins regulate cells by actions outside of caveolae? Trends Cell Biol 17:51–57

    Article  CAS  PubMed  Google Scholar 

  23. Head BP, Patel HH, Roth DM, Murray F, Swaney JS, Niesman IR, Farquhar MG, Insel PA (2006) Microtubules and actin microfilaments regulate lipid raft/caveolae localization of adenylyl cyclase signaling components. J Biol Chem 281:26391–26399

    Article  CAS  PubMed  Google Scholar 

  24. Boeckers TM (2006) The postsynaptic density. Cell Tissue Res 326:409–422

    Article  CAS  PubMed  Google Scholar 

  25. Perez AS, Bredt DS (1998) The N-terminal PDZ-containing region of postsynaptic density-95 mediates association with caveolar-like lipid domains. Neurosci Lett 258:121–123

    Article  CAS  PubMed  Google Scholar 

  26. Murata M, Peranen J, Schreiner R, Wieland F, Kurzchalia TV, Simons K (1995) VIP21/caveolin is a cholesterol-binding protein. Proc Natl Acad Sci USA 92:10339–10343

    Article  CAS  PubMed  Google Scholar 

  27. Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A, Pfrieger FW (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354–1357

    Article  CAS  PubMed  Google Scholar 

  28. Willmann R, Pun S, Stallmach L, Sadasivam G, Santos AF, Caroni P, Fuhrer C (2006) Cholesterol and lipid microdomains stabilize the postsynapse at the neuromuscular junction. EMBO J 25:4050–4060

    Article  CAS  PubMed  Google Scholar 

  29. Oshikawa J, Otsu K, Toya Y, Tsunematsu T, Hankins R, Kawabe J, Minamisawa S, Umemura S, Hagiwara Y, Ishikawa Y (2004) Insulin resistance in skeletal muscles of caveolin-3-null mice. Proc Natl Acad Sci USA 101:12670–12675

    Article  PubMed  Google Scholar 

  30. Kong MM, Hasbi A, Mattocks M, Fan T, O’Dowd BF, George SR (2007) Regulation of D1 dopamine receptor trafficking and signaling by caveolin-1. Mol Pharmacol 72:1157–1170

    Article  CAS  PubMed  Google Scholar 

  31. Shmuel M, Nodel-Berner E, Hyman T, Rouvinski A, Altschuler Y (2007) Caveolin 2 regulates endocytosis and trafficking of the M1 muscarinic receptor in MDCK epithelial cells. Mol Biol Cell 18:1570–1585

    Article  CAS  PubMed  Google Scholar 

  32. Wyse BD, Prior IA, Qian H, Morrow IC, Nixon S, Muncke C, Kurzchalia TV, Thomas WG, Parton RG, Hancock JF (2003) Caveolin interacts with the angiotensin II type 1 receptor during exocytic transport but not at the plasma membrane. J Biol Chem 278:23738–23746

    Article  CAS  PubMed  Google Scholar 

  33. Syme CA, Zhang L, Bisello A (2006) Caveolin-1 regulates cellular trafficking and function of the glucagon-like peptide 1 receptor. Mol Endocrinol 20:3400–3411

    Article  CAS  PubMed  Google Scholar 

  34. Lajoie P, Nabi IR (2007) Regulation of raft-dependent endocytosis. J Cell Mol Med 11:644–653

    Article  CAS  PubMed  Google Scholar 

  35. Pelkmans L, Helenius A (2002) Endocytosis via caveolae. Traffic 3:311–320

    Article  CAS  PubMed  Google Scholar 

  36. Hommelgaard AM, Roepstorff K, Vilhardt F, Torgersen ML, Sandvig K, van Deurs B (2005) Caveolae: stable membrane domains with a potential for internalization. Traffic 6:720–724

    Article  CAS  PubMed  Google Scholar 

  37. Becher A, McIlhinney RA (2005) Consequences of lipid raft association on G-protein-coupled receptor function. Biochem Soc Symp 72:151–164

    CAS  PubMed  Google Scholar 

  38. de Weerd WF, Leeb-Lundberg LM (1997) Bradykinin sequesters B2 bradykinin receptors and the receptor-coupled Galpha subunits Galphaq and Galphai in caveolae in DDT1 MF-2 smooth muscle cells. J Biol Chem 272:17858–17866

    Article  PubMed  Google Scholar 

  39. Whistler JL, Chuang HH, Chu P, Jan LY, von Zastrow M (1999) Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Neuron 23:737–746

    Article  CAS  PubMed  Google Scholar 

  40. Bhatnagar A, Sheffler DJ, Kroeze WK, Compton-Toth B, Roth BL (2004) Caveolin-1 interacts with 5-HT2A serotonin receptors and profoundly modulates the signaling of selected Galphaq-coupled protein receptors. J Biol Chem 279:34614–34623

    Article  CAS  PubMed  Google Scholar 

  41. Toran-Allerand CD (2004) Minireview: a plethora of estrogen receptors in the brain: where will it end? Endocrinology 145:1069–1074

    Article  CAS  PubMed  Google Scholar 

  42. Boulware MI, Weick JP, Becklund BR, Kuo SP, Groth RD, Mermelstein PG (2005) Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein. J Neurosci 25:5066–5078

    Article  CAS  PubMed  Google Scholar 

  43. McKenna NJ, Lanz RB, O’Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20:321–344

    Article  CAS  PubMed  Google Scholar 

  44. McInerney EM, Weis KE, Sun J, Mosselman S, Katzenellenbogen BS (1998) Transcription activation by the human estrogen receptor subtype beta (ER beta) studied with ER beta and ER alpha receptor chimeras. Endocrinology 139:4513–4522

    Article  CAS  PubMed  Google Scholar 

  45. Sheldahl LC, Shapiro RA, Bryant DN, Koerner IP, Dorsa DM (2008) Estrogen induces rapid translocation of estrogen receptor beta, but not estrogen receptor alpha, to the neuronal plasma membrane. Neuroscience 153:751–761

    Article  CAS  PubMed  Google Scholar 

  46. Francesconi A, Kumari R, Zukin RS (2009) Regulation of group I metabotropic glutamate receptor trafficking and signaling by the caveolar/lipid raft pathway. J Neurosci 29:3590–3602

    Article  CAS  PubMed  Google Scholar 

  47. Couchoux H, Allard B, Legrand C, Jacquemond V, Berthier C (2007) Loss of caveolin-3 induced by the dystrophy-associated P104L mutation impairs L-type calcium channel function in mouse skeletal muscle cells. J Physiol 580:745–754

    Article  CAS  PubMed  Google Scholar 

  48. Cheng X, Jaggar JH (2006) Genetic ablation of caveolin-1 modifies Ca2+ spark coupling in murine arterial smooth muscle cells. Am J Physiol Heart Circ Physiol 290:H2309–H2319

    Article  CAS  PubMed  Google Scholar 

  49. Daniel EE, Eteraf T, Sommer B, Cho WJ, Elyazbi A (2009) The role of caveolae and caveolin 1 in calcium handling in pacing and contraction of mouse intestine. J Cell Mol Med 13:352–364

    Article  CAS  PubMed  Google Scholar 

  50. Balijepalli RC, Foell JD, Hall DD, Hell JW, Kamp TJ (2006) Localization of cardiac L-type Ca(2+) channels to a caveolar macromolecular signaling complex is required for beta(2)-adrenergic regulation. Proc Natl Acad Sci USA 103:7500–7505

    Article  CAS  PubMed  Google Scholar 

  51. Head BP, Patel HH, Tsutsumi YM, Hu Y, Mejia T, Mora RC, Insel PA, Roth DM, Drummond JC, Patel PM (2008) Caveolin-1 expression is essential for N-methyl-d-aspartate receptor-mediated Src and extracellular signal-regulated kinase 1/2 activation and protection of primary neurons from ischemic cell death. FASEB J 22:828–840

    Article  CAS  PubMed  Google Scholar 

  52. Couet J, Sargiacomo M, Lisanti MP (1997) Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities. J Biol Chem 272:30429–30438

    Article  CAS  PubMed  Google Scholar 

  53. Ramirez CM, Gonzalez M, Diaz M, Alonso R, Ferrer I, Santpere G, Puig B, Meyer G, Marin R (2009) VDAC and ERalpha interaction in caveolae from human cortex is altered in Alzheimer’s disease. Mol Cell Neurosci 42:172–183

    Article  CAS  PubMed  Google Scholar 

  54. Ferrer I (2009) Altered mitochondria, energy metabolism, voltage-dependent anion channel, and lipid rafts converge to exhaust neurons in Alzheimer’s disease. J Bioenerg Biomembr 41:425–431

    Article  CAS  PubMed  Google Scholar 

  55. Kanai Y, Hediger MA (1992) Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360:467–471

    Article  CAS  PubMed  Google Scholar 

  56. Gonzalez MI, Krizman-Genda E, Robinson MB (2007) Caveolin-1 regulates the delivery and endocytosis of the glutamate transporter, excitatory amino acid carrier 1. J Biol Chem 282:29855–29865

    Article  CAS  PubMed  Google Scholar 

  57. Fecchi K, Volonte D, Hezel MP, Schmeck K, Galbiati F (2006) Spatial and temporal regulation of GLUT4 translocation by flotillin-1 and caveolin-3 in skeletal muscle cells. FASEB J 20:705–707

    CAS  PubMed  Google Scholar 

  58. Butchbach ME, Tian G, Guo H, Lin CL (2004) Association of excitatory amino acid transporters, especially EAAT2, with cholesterol-rich lipid raft microdomains: importance for excitatory amino acid transporter localization and function. J Biol Chem 279:34388–34396

    Article  CAS  PubMed  Google Scholar 

  59. McFarland MJ, Porter AC, Rakhshan FR, Rawat DS, Gibbs RA, Barker EL (2004) A role for caveolae/lipid rafts in the uptake and recycling of the endogenous cannabinoid anandamide. J Biol Chem 279:41991–41997

    Article  CAS  PubMed  Google Scholar 

  60. Samuvel DJ, Jayanthi LD, Bhat NR, Ramamoorthy S (2005) A role for p38 mitogen-activated protein kinase in the regulation of the serotonin transporter: evidence for distinct cellular mechanisms involved in transporter surface expression. J Neurosci 25:29–41

    Article  CAS  PubMed  Google Scholar 

  61. Harmey JH, Doyle D, Brown V, Rogers MS (1995) The cellular isoform of the prion protein, PrPc, is associated with caveolae in mouse neuroblastoma (N2a) cells. Biochem Biophys Res Commun 210:753–759

    Article  CAS  PubMed  Google Scholar 

  62. Mouillet-Richard S, Ermonval M, Chebassier C, Laplanche JL, Lehmann S, Launay JM, Kellermann O (2000) Signal transduction through prion protein. Science 289:1925–1928

    Article  CAS  PubMed  Google Scholar 

  63. Pantera B, Bini C, Cirri P, Paoli P, Camici G, Manao G, Caselli A (2009) PrPc activation induces neurite outgrowth and differentiation in PC12 cells: role for caveolin-1 in the signal transduction pathway. J Neurochem 110:194–207

    Article  CAS  PubMed  Google Scholar 

  64. Pietri M, Caprini A, Mouillet-Richard S, Pradines E, Ermonval M, Grassi J, Kellermann O, Schneider B (2006) Overstimulation of PrPC signaling pathways by prion peptide 106–126 causes oxidative injury of bioaminergic neuronal cells. J Biol Chem 281:28470–28479

    Article  CAS  PubMed  Google Scholar 

  65. Toni M, Spisni E, Griffoni C, Santi S, Riccio M, Lenaz P, Tomasi V (2006) Cellular prion protein and caveolin-1 interaction in a neuronal cell line precedes fyn/erk 1/2 signal transduction. J Biomed Biotechnol 2006:69469

    PubMed  Google Scholar 

  66. Engelman JA, Chu C, Lin A, Jo H, Ikezu T, Okamoto T, Kohtz DS, Lisanti MP (1998) Caveolin-mediated regulation of signaling along the p42/44 MAP kinase cascade in vivo. A role for the caveolin-scaffolding domain. FEBS Lett 428:205–211

    Article  CAS  PubMed  Google Scholar 

  67. Zhang W, Razani B, Altschuler Y, Bouzahzah B, Mostov KE, Pestell RG, Lisanti MP (2000) Caveolin-1 inhibits epidermal growth factor-stimulated lamellipod extension and cell migration in metastatic mammary adenocarcinoma cells (MTLn3). Transformation suppressor effects of adenovirus-mediated gene delivery of caveolin-1. J Biol Chem 275:20717–20725

    Article  CAS  PubMed  Google Scholar 

  68. Allen JA, Yu JZ, Dave RH, Bhatnagar A, Roth BL, Rasenick MM (2009) Caveolin-1 and lipid microdomains regulate Gs trafficking and attenuate Gs/adenylyl cyclase signaling. Mol Pharmacol 76:1082–1093

    Article  CAS  PubMed  Google Scholar 

  69. Kang MJ, Seo JS, Park WY (2006) Caveolin-1 inhibits neurite growth by blocking Rac1/Cdc42 and p21-activated kinase 1 interactions. Neuroreport 17:823–827

    Article  CAS  PubMed  Google Scholar 

  70. Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87

    Article  CAS  PubMed  Google Scholar 

  71. Garcia-Cardena G, Martasek P, Masters BS, Skidd PM, Couet J, Li S, Lisanti MP, Sessa WC (1997) Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem 272:25437–25440

    Article  CAS  PubMed  Google Scholar 

  72. Sato Y, Sagami I, Shimizu T (2004) Identification of caveolin-1-interacting sites in neuronal nitric-oxide synthase. Molecular mechanism for inhibition of NO formation. J Biol Chem 279:8827–8836

    Article  CAS  PubMed  Google Scholar 

  73. Shen J, Lee W, Li Y, Lau CF, Ng KM, Fung ML, Liu KJ (2008) Interaction of caveolin-1, nitric oxide, and nitric oxide synthases in hypoxic human SK-N-MC neuroblastoma cells. J Neurochem 107:478–487

    Article  CAS  PubMed  Google Scholar 

  74. Gaudreault SB, Chabot C, Gratton JP, Poirier J (2004) The caveolin scaffolding domain modifies 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor binding properties by inhibiting phospholipase A2 activity. J Biol Chem 279:356–362

    Article  CAS  PubMed  Google Scholar 

  75. Massicotte G, Baudry M (1990) Modulation of -alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/quisqualate receptors by phospholipase A2 treatment. Neurosci Lett 118:245–248

    Article  CAS  PubMed  Google Scholar 

  76. Catania MV, Hollingsworth Z, Penney JB, Young AB (1993) Phospholipase A2 modulates different subtypes of excitatory amino acid receptors: autoradiographic evidence. J Neurochem 60:236–245

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church Street S.E., Minneapolis, MN, 5455, USA

    Christopher M. Stern & Paul G. Mermelstein

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Stern, C.M., Mermelstein, P.G. Caveolin regulation of neuronal intracellular signaling. Cell. Mol. Life Sci. 67, 3785–3795 (2010). https://doi.org/10.1007/s00018-010-0447-y

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