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Biochem J. Apr 15, 1999; 339(Pt 2): 453–461.
PMCID: PMC1220177

Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway.

Abstract

Activation of certain phosphoinositidase-C-linked cell-surface receptors is known to cause an acceleration of the proteolysis of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptors and, thus, lead to Ins(1,4,5)P3-receptor down-regulation. In the current study we have sought to determine whether the ubiquitin/proteasome pathway is involved in this adaptive response. The data presented show (i) that activation of phosphoinositidase-C-linked receptors causes Ins(1,4,5)P3-receptor ubiquitination in a range of cell types (AR4-2J cells, INS-1 cells and rat cerebellar granule cells), (ii) that the Ins(1,4,5)P3-receptor down-regulation induced by activation of these receptors is blocked by proteasome inhibitors, (iii) that all known Ins(1,4,5)P3 receptors (types I, II and III) are substrates for ubiquitination, (iv) that ubiquitination occurs while Ins(1,4,5)P3 receptors are membrane-bound, (v) that Ins(1,4, 5)P3-receptor ubiquitination and down-regulation are stimulated only by those agonists that elevate Ins(1,4,5)P3 concentration persistently, and (vi) that a portion of cellular Ins(1,4,5)P3 receptors (those that are not type-I-receptor-associated) can be resistant to ubiquitination and degradation. In total these data indicate that the ubiquitin/proteasome pathway mediates Ins(1,4, 5)P3-receptor down-regulation and suggest that ubiquitination is stimulated by the binding of Ins(1,4,5)P3 to its receptor.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Joseph SK. The inositol triphosphate receptor family. Cell Signal. 1996 Jan;8(1):1–7. [PubMed]
  • Yoshida Y, Imai S. Structure and function of inositol 1,4,5-trisphosphate receptor. Jpn J Pharmacol. 1997 Jun;74(2):125–137. [PubMed]
  • Wojcikiewicz RJ. Type I, II, and III inositol 1,4,5-trisphosphate receptors are unequally susceptible to down-regulation and are expressed in markedly different proportions in different cell types. J Biol Chem. 1995 May 12;270(19):11678–11683. [PubMed]
  • De Smedt H, Missiaen L, Parys JB, Henning RH, Sienaert I, Vanlingen S, Gijsens A, Himpens B, Casteels R. Isoform diversity of the inositol trisphosphate receptor in cell types of mouse origin. Biochem J. 1997 Mar 1;322(Pt 2):575–583. [PMC free article] [PubMed]
  • Monkawa T, Miyawaki A, Sugiyama T, Yoneshima H, Yamamoto-Hino M, Furuichi T, Saruta T, Hasegawa M, Mikoshiba K. Heterotetrameric complex formation of inositol 1,4,5-trisphosphate receptor subunits. J Biol Chem. 1995 Jun 16;270(24):14700–14704. [PubMed]
  • Joseph SK, Lin C, Pierson S, Thomas AP, Maranto AR. Heteroligomers of type-I and type-III inositol trisphosphate receptors in WB rat liver epithelial cells. J Biol Chem. 1995 Oct 6;270(40):23310–23316. [PubMed]
  • Wojcikiewicz RJ, He Y. Type I, II and III inositol 1,4,5-trisphosphate receptor co-immunoprecipitation as evidence for the existence of heterotetrameric receptor complexes. Biochem Biophys Res Commun. 1995 Aug 4;213(1):334–341. [PubMed]
  • Wojcikiewicz RJ, Nahorski SR. Chronic muscarinic stimulation of SH-SY5Y neuroblastoma cells suppresses inositol 1,4,5-trisphosphate action. Parallel inhibition of inositol 1,4,5-trisphosphate-induced Ca2+ mobilization and inositol 1,4,5-trisphosphate binding. J Biol Chem. 1991 Nov 25;266(33):22234–22241. [PubMed]
  • Wojcikiewicz RJ, Furuichi T, Nakade S, Mikoshiba K, Nahorski SR. Muscarinic receptor activation down-regulates the type I inositol 1,4,5-trisphosphate receptor by accelerating its degradation. J Biol Chem. 1994 Mar 18;269(11):7963–7969. [PubMed]
  • Bokkala S, Joseph SK. Angiotensin II-induced down-regulation of inositol trisphosphate receptors in WB rat liver epithelial cells. Evidence for involvement of the proteasome pathway. J Biol Chem. 1997 May 9;272(19):12454–12461. [PubMed]
  • Sipma H, Deelman L, Smedt HD, Missiaen L, Parys JB, Vanlingen S, Henning RH, Casteels R. Agonist-induced down-regulation of type 1 and type 3 inositol 1,4,5-trisphosphate receptors in A7r5 and DDT1 MF-2 smooth muscle cells. Cell Calcium. 1998 Jan;23(1):11–21. [PubMed]
  • Wojcikiewicz RJ, Oberdorf JA. Degradation of inositol 1,4,5-trisphosphate receptors during cell stimulation is a specific process mediated by cysteine protease activity. J Biol Chem. 1996 Jul 12;271(28):16652–16655. [PubMed]
  • Sorimachi H, Ishiura S, Suzuki K. Structure and physiological function of calpains. Biochem J. 1997 Dec 15;328(Pt 3):721–732. [PMC free article] [PubMed]
  • Magnusson A, Haug LS, Walaas SI, Ostvold AC. Calcium-induced degradation of the inositol (1,4,5)-trisphosphate receptor/Ca(2+)-channel. FEBS Lett. 1993 Jun 1;323(3):229–232. [PubMed]
  • Varshavsky A. The ubiquitin system. Trends Biochem Sci. 1997 Oct;22(10):383–387. [PubMed]
  • Haas AL, Siepmann TJ. Pathways of ubiquitin conjugation. FASEB J. 1997 Dec;11(14):1257–1268. [PubMed]
  • Fenteany G, Schreiber SL. Lactacystin, proteasome function, and cell fate. J Biol Chem. 1998 Apr 10;273(15):8545–8548. [PubMed]
  • Mellgren RL. Specificities of cell permeant peptidyl inhibitors for the proteinase activities of mu-calpain and the 20 S proteasome. J Biol Chem. 1997 Nov 21;272(47):29899–29903. [PubMed]
  • Coux O, Tanaka K, Goldberg AL. Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem. 1996;65:801–847. [PubMed]
  • Larsen CN, Finley D. Protein translocation channels in the proteasome and other proteases. Cell. 1997 Nov 14;91(4):431–434. [PubMed]
  • Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R. Structure of 20S proteasome from yeast at 2.4 A resolution. Nature. 1997 Apr 3;386(6624):463–471. [PubMed]
  • Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D, Goldberg AL. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994 Sep 9;78(5):761–771. [PubMed]
  • Sommer T, Wolf DH. Endoplasmic reticulum degradation: reverse protein flow of no return. FASEB J. 1997 Dec;11(14):1227–1233. [PubMed]
  • Kopito RR. ER quality control: the cytoplasmic connection. Cell. 1997 Feb 21;88(4):427–430. [PubMed]
  • Mori S, Heldin CH, Claesson-Welsh L. Ligand-induced polyubiquitination of the platelet-derived growth factor beta-receptor. J Biol Chem. 1992 Mar 25;267(9):6429–6434. [PubMed]
  • Cenciarelli C, Hou D, Hsu KC, Rellahan BL, Wiest DL, Smith HT, Fried VA, Weissman AM. Activation-induced ubiquitination of the T cell antigen receptor. Science. 1992 Aug 7;257(5071):795–797. [PubMed]
  • Gardner R, Cronin S, Leader B, Rine J, Hampton R, Leder B. Sequence determinants for regulated degradation of yeast 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. Mol Biol Cell. 1998 Sep;9(9):2611–2626. [PMC free article] [PubMed]
  • Schwartz AL, Trausch JS, Ciechanover A, Slot JW, Geuze H. Immunoelectron microscopic localization of the ubiquitin-activating enzyme E1 in HepG2 cells. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5542–5546. [PMC free article] [PubMed]
  • Palmer A, Rivett AJ, Thomson S, Hendil KB, Butcher GW, Fuertes G, Knecht E. Subpopulations of proteasomes in rat liver nuclei, microsomes and cytosol. Biochem J. 1996 Jun 1;316(Pt 2):401–407. [PMC free article] [PubMed]
  • Asfari M, Janjic D, Meda P, Li G, Halban PA, Wollheim CB. Establishment of 2-mercaptoethanol-dependent differentiated insulin-secreting cell lines. Endocrinology. 1992 Jan;130(1):167–178. [PubMed]
  • Wojcikiewicz RJ, Tobin AB, Nahorski SR. Muscarinic receptor-mediated inositol 1,4,5-trisphosphate formation in SH-SY5Y neuroblastoma cells is regulated acutely by cytosolic Ca2+ and by rapid desensitization. J Neurochem. 1994 Jul;63(1):177–185. [PubMed]
  • Berleth ES, Pickart CM. Mechanism of ubiquitin conjugating enzyme E2-230K: catalysis involving a thiol relay? Biochemistry. 1996 Feb 6;35(5):1664–1671. [PubMed]
  • Menniti FS, Takemura H, Oliver KG, Putney JW., Jr Different modes of regulation for receptors activating phospholipase C in the rat pancreatoma cell line AR4-2J. Mol Pharmacol. 1991 Nov;40(5):727–733. [PubMed]
  • Simeone DM, Yule DI, Logsdon CD, Williams JA. Ca2+ signaling through secretagogue and growth factor receptors on pancreatic AR42J cells. Regul Pept. 1995 Jan 26;55(2):197–206. [PubMed]
  • Wojcikiewicz RJ, Tobin AB, Nahorski SR. Desensitization of cell signalling mediated by phosphoinositidase C. Trends Pharmacol Sci. 1993 Jul;14(7):279–285. [PubMed]
  • Mathias RS, Mikoshiba K, Michikawa T, Miyawaki A, Ives HE. IP3 receptor blockade fails to prevent intracellular Ca2+ release by ET-1 and alpha-thrombin. Am J Physiol. 1998 Jun;274(6 Pt 1):C1456–C1465. [PubMed]
  • Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D. Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J. 1997 Nov 3;16(21):6325–6336. [PMC free article] [PubMed]
  • Wilkinson KD. Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. FASEB J. 1997 Dec;11(14):1245–1256. [PubMed]
  • Thastrup O, Cullen PJ, Drøbak BK, Hanley MR, Dawson AP. Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)-ATPase. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2466–2470. [PMC free article] [PubMed]
  • Oberdorf J, Vallano ML, Wojcikiewicz RJ. Expression and regulation of types I and II inositol 1,4,5-trisphosphate receptors in rat cerebellar granule cell preparations. J Neurochem. 1997 Nov;69(5):1897–1903. [PubMed]
  • Klausner RD, Sitia R. Protein degradation in the endoplasmic reticulum. Cell. 1990 Aug 24;62(4):611–614. [PubMed]
  • Plemper RK, Egner R, Kuchler K, Wolf DH. Endoplasmic reticulum degradation of a mutated ATP-binding cassette transporter Pdr5 proceeds in a concerted action of Sec61 and the proteasome. J Biol Chem. 1998 Dec 4;273(49):32848–32856. [PubMed]
  • Gutkind JS. The pathways connecting G protein-coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascades. J Biol Chem. 1998 Jan 23;273(4):1839–1842. [PubMed]
  • Mignery GA, Südhof TC. The ligand binding site and transduction mechanism in the inositol-1,4,5-triphosphate receptor. EMBO J. 1990 Dec;9(12):3893–3898. [PMC free article] [PubMed]
  • Zhu CC, Furuichi T, Mikoshiba K, Wojcikiewicz RJ. Inositol 1,4,5-trisphosphate receptor down-regulation is activated directly by inositol 1,4,5-trisphosphate binding. Studies with binding-defective mutant receptors. J Biol Chem. 1999 Feb 5;274(6):3476–3484. [PubMed]
  • Dürr G, Strayle J, Plemper R, Elbs S, Klee SK, Catty P, Wolf DH, Rudolph HK. The medial-Golgi ion pump Pmr1 supplies the yeast secretory pathway with Ca2+ and Mn2+ required for glycosylation, sorting, and endoplasmic reticulum-associated protein degradation. Mol Biol Cell. 1998 May;9(5):1149–1162. [PMC free article] [PubMed]
  • Watras J, Moraru I, Costa DJ, Kindman LA. Two inositol 1,4,5-trisphosphate binding sites in rat basophilic leukemia cells: relationship between receptor occupancy and calcium release. Biochemistry. 1994 Nov 29;33(47):14359–14367. [PubMed]
  • Wilson BS, Pfeiffer JR, Smith AJ, Oliver JM, Oberdorf JA, Wojcikiewicz RJ. Calcium-dependent clustering of inositol 1,4,5-trisphosphate receptors. Mol Biol Cell. 1998 Jun;9(6):1465–1478. [PMC free article] [PubMed]

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