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• W2412031353 abstract "The content of spermidine and spermine in mammalian cells has important roles in protein and nucleic acid synthesis and structure, protection from oxidative damage, activity of ion channels, cell proliferation, differentiation, and apoptosis. Spermidine is essential for viability and acts as the precursor of hypusine, a post-translational addition to eIF5A allowing the translation of mRNAs encoding proteins containing polyproline tracts. Studies with Gy mice and human patients with the very rare X-linked genetic condition Snyder-Robinson syndrome that both lack spermine synthase show clearly that the correct spermine:spermidine ratio is critical for normal growth and development. The content of spermidine and spermine in mammalian cells has important roles in protein and nucleic acid synthesis and structure, protection from oxidative damage, activity of ion channels, cell proliferation, differentiation, and apoptosis. Spermidine is essential for viability and acts as the precursor of hypusine, a post-translational addition to eIF5A allowing the translation of mRNAs encoding proteins containing polyproline tracts. Studies with Gy mice and human patients with the very rare X-linked genetic condition Snyder-Robinson syndrome that both lack spermine synthase show clearly that the correct spermine:spermidine ratio is critical for normal growth and development. There is very strong experimental evidence that maintenance of a normal polyamine content is essential for a wide variety of basic cellular functions. (a) Their content is very tightly controlled with the key enzymes in biosynthesis and interconversion having multiple levels of regulation in response to hormonal stimulation and polyamine content. (b) With the use of specific inhibitors of polyamine biosynthesis, it is relatively easy to substantially deplete cellular polyamine content, and striking effects have been observed on numerous critical cell functions including growth, differentiation, apoptosis, motility, and resistance to oxidative and other stresses. (c) The interaction of polyamines with nucleic acids and proteins can affect both structure and stability. Binding of polyamines to DNA affects its structure and stability (1.Iacomino G. Picariello G. D'Agostino L. DNA and nuclear aggregates of polyamines.Biochim. Biophys. Acta. 2012; 1823: 1745-1755Crossref PubMed Scopus (67) Google Scholar). The importance of the effects on DNA stability is emphasized by the presence in acute thermophiles of high levels of polyamines, including branched chain molecules and longer linear amines than those found in mammals. These allow their survival at elevated temperatures (2.Terui Y. Ohnuma M. Hiraga K. Kawashima E. Oshima T. Stabilization of nucleic acids by unusual polyamines produced by an extreme thermophile.Biochem. J. 2005; 388: 427-433Crossref PubMed Scopus (85) Google Scholar). The majority of cellular polyamines are bound to RNA, and the changes in structure produced by binding to ribosomes, tRNA, and some mRNAs with particular sequences influence protein synthesis in multiple ways (3.Igarashi K. Kashiwagi K. Modulation of cellular function by polyamines.Int. J. Biochem. Cell Biol. 2010; 42: 39-51Crossref PubMed Scopus (590) Google Scholar). Interactions of polyamines with proteins forming microtubules can influence their assembly and shape (4.Ojeda-Lopez M.A. Needleman D.J. Song C. Ginsburg A. Kohl P.A. Li Y. Miller H.P. Wilson L. Raviv U. Choi M.C. Safinya C.R. Transformation of taxol-stabilized microtubules into inverted tubulin tubules triggered by a tubulin conformation switch.Nat. Mater. 2014; 13: 195-203Crossref PubMed Scopus (46) Google Scholar), and interaction with protein membrane receptors can have profound effects on crucial receptors. It should be stressed that these observations, although confirming that polyamines are essential cellular components, do not indicate that the polyamines necessarily play regulatory roles. Experimental support for such regulation would require the demonstration that physiological rather than pharmacological changes in polyamine content are associated with alterations in function, and this has rarely been demonstrated rigorously. It is not possible in a brief review to describe all of the actions that have been assigned to polyamines. The focus is on those functions that have been demonstrated to influence animal growth and development with particular emphasis on the phenotypes revealed by experimental animals and humans with an inborn error of metabolism leading to a reduction in spermine. The polyamines synthesized by mammals are the triamine spermidine, the tetramine spermine, and their precursor putrescine (Fig. 1). Traces from dietary sources of other polyamines such as agmatine may be present in human tissues, but there is no convincing evidence that these play any physiological role. In contrast, the native polyamines are essential for viability. The polyamine biosynthetic and interconversion pathway in mammals is well established and has been described in multiple reviews (5.Pegg A.E. Mammalian polyamine metabolism and function.IUBMB Life. 2009; 61: 880-894Crossref PubMed Scopus (515) Google Scholar, 6.Battaglia V. DeStefano Shields C. Murray-Stewart T. Casero Jr., R.A. Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention.Amino Acids. 2014; 46: 511-519Crossref PubMed Scopus (59) Google Scholar). Putrescine is formed by ornithine decarboxylase (ODC), 2The abbreviations and trivial names used are: ODC, ornithine decarboxylase; AdoMetDC, S-adenosylmethionine decarboxylase; dcAdoMet, decarboxylated S-adenosylmethionine; SSAT, spermidine/spermine-N1-acetyltranferase; DFMO, α-difluoromethylornithine; hypusine, Nϵ-(4-amino-2-hydroxybutyl)lysine; SRS, Snyder-Robinson syndrome; TRPC, transient receptor potential cation. and S-adenosylmethionine decarboxylase (AdoMetDC) produces dcAdoMet (Fig. 1). Inactivation of the ODC or AdoMetDC genes or treatment with ODC inhibitors results in lethality early in embryonic development (7.Fozard J.R. Part M.L. Prakash N.J. Grove J. Schechter P.J. Sjoerdsma A. Koch-Weser J. l-Ornithine decarboxylase: an essential role in early mammalian embryogenesis.Science. 1980; 208: 505-508Crossref PubMed Scopus (0) Google Scholar, 8.Pendeville H. Carpino N. Marine J.C. Takahashi Y. Muller M. Martial J.A. Cleveland J.L. The ornithine decarboxylase gene is essential for cell survival during early murine development.Mol. Cell. Biol. 2001; 21: 6549-6558Crossref PubMed Scopus (189) Google Scholar, 9.Nishimura K. Nakatsu F. Kashiwagi K. Ohno H. Saito T. Igarashi K. Essential role of S-adenosylmethionine decarboxylase in mouse embryonic development.Genes Cells. 2002; 7: 41-47Crossref PubMed Scopus (97) Google Scholar). The contents of ODC and AdoMetDC are very highly regulated at multiple levels in response to stimuli controlling polyamine levels. The supply of dcAdoMet limits the formation of the higher polyamines by spermidine synthase and spermine synthase (Fig. 1). In mammals, these two aminopropyltransferases are highly specific with regard to their amine substrate (10.Pegg A.E. Michael A.J. Spermine synthase.Cell. Mol. Life Sci. 2010; 67: 113-121Crossref PubMed Scopus (106) Google Scholar, 11.Pegg A.E. The function of spermine.IUBMB Life. 2014; 66: 8-18Crossref PubMed Scopus (137) Google Scholar). Restrictions in the active site in spermidine synthase will not allow the binding of the larger spermidine at the putrescine substrate site (12.Wu H. Min J. Ikeguchi Y. Zeng H. Dong A. Loppnau P. Pegg A.E. Plotnikov A.N. Structure and mechanism of spermidine synthases.Biochemistry. 2007; 46: 8331-8339Crossref PubMed Scopus (73) Google Scholar), and the corresponding site in spermine synthase exclusively favors spermidine as substrate over putrescine (13.Wu H. Min J. Zeng H. McCloskey D.E. Ikeguchi Y. Loppnau P. Michael A.J. Pegg A.E. Plotnikov A.N. Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism.J. Biol. Chem. 2008; 283: 16135-16146Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). The aminopropyltransferase reactions are effectively irreversible, but the polyamines can be interconverted by oxidative degradation directly via spermine oxidase or by acetylpolyamine oxidase after acetylation via spermidine/spermine-N1-acetyltranferase (SSAT) (6.Battaglia V. DeStefano Shields C. Murray-Stewart T. Casero Jr., R.A. Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention.Amino Acids. 2014; 46: 511-519Crossref PubMed Scopus (59) Google Scholar, 14.Pegg A.E. Spermidine/spermine N1-acetyltransferase: a key metabolic regulator.Am. J. Physiol. Endocrinol. Metab. 2008; 294: E995-1010Crossref PubMed Scopus (248) Google Scholar). The latter pathway is effectively controlled by the content of SSAT, a highly regulated cytosolic enzyme, which responds to high polyamine levels (14.Pegg A.E. Spermidine/spermine N1-acetyltransferase: a key metabolic regulator.Am. J. Physiol. Endocrinol. Metab. 2008; 294: E995-1010Crossref PubMed Scopus (248) Google Scholar). Polyamines are essential for cell proliferation. Polyamine content is higher in rapidly growing tissues, and regenerative and growth-promoting hormonal stimuli enhance polyamine synthesis and content (15.Raina A. Jänne J. Siimes M. Stimulation of polyamine synthesis in relation to nucleic acids in regenerating rat liver.Biochim. Biophys. Acta. 1966; 123: 197-201Crossref PubMed Scopus (134) Google Scholar, 16.Russell D. Snyder S.H. Amine synthesis in rapidly growing tissues: ornithine decarboxylase activity in regenerating rat liver, chick embryo, and various tumors.Proc. Natl. Acad. Sci. U.S.A. 1968; 60: 1420-1427Crossref PubMed Scopus (883) Google Scholar, 17.Pegg A.E. Lockwood D.H. Williams-Ashman H.G. Concentrations of putrescine and polyamines and their enzymic synthesis during androgen-induced prostatic growth.Biochem. J. 1970; 117: 17-31Crossref PubMed Scopus (234) Google Scholar). Treatment of cultured cells with ODC inhibitors such as α-difluoromethylornithine (DFMO) led to a virtually complete loss of putrescine and spermidine but little change in spermine and halted cell proliferation (18.Mamont P.S. Böhlen P. McCann P.P. Bey P. Schuber F. Tardif C. α-Methyl ornithine, a potent competitive inhibitor of ornithine decarboxylase, blocks proliferation of rat hepatoma cells in culture.Proc. Natl. Acad. Sci. U.S.A. 1976; 73: 1626-1630Crossref PubMed Scopus (215) Google Scholar). Cytostasis was reversed by the provision of exogenous putrescine or spermidine, which restored a normal spermidine content. Even after long exposure, the effects of DFMO were cytostatic rather than cytotoxic. This may be due to the presence of residual spermine and hypusinated eIF5A (see below), which both decline very slowly in quiescent cells. When treatments were used that depleted both spermidine and spermine, there were progressive decreases in both proliferation and viability and increased apoptosis, which were prevented by the provision of exogenous polyamines (19.Mamont P.S. Siat M. Joder-Ohlenbusch A.M. Bernhardt A. Casara P. Effect of (2R, 5R)-6-heptyne-2, 5-diamine, a potent inhibitor of l-ornithine decarboxylase, on rat hepatoma cells cultured in vitro.Eur. J. Biochem. 1984; 142: 457-463Crossref PubMed Scopus (47) Google Scholar, 20.He Y. Shimogori T. Kashiwagi K. Shirahata A. Igarashi K. Inhibition of cell growth by combination of α-difluoromethylornithine and an inhibitor of spermine synthase.J. Biochem. 1995; 117: 824-829Crossref PubMed Scopus (16) Google Scholar, 21.Mandal S. Mandal A. Park M.H. Depletion of the polyamines spermidine and spermine by overexpression of spermidine/spermine N1-acetyltransferase 1 (SAT1) leads to mitochondria-mediated apoptosis in mammalian cells.Biochem. J. 2015; 468: 435-447Crossref PubMed Scopus (39) Google Scholar). Studies with cultured cells from rodents lacking spermine synthase confirmed that a normal growth rate was maintained in cells with elevated spermidine levels but no spermine (22.Mackintosh C.A. Pegg A.E. Effect of spermine synthase deficiency on polyamine biosynthesis and content in mice and embryonic fibroblasts and the sensitivity of fibroblasts to 1,3-bis(2-chloroethyl)-N-nitrosourea.Biochem. J. 2000; 351: 439-447Crossref PubMed Scopus (48) Google Scholar, 23.Nilsson J. Gritli-Linde A. Heby O. Skin fibroblasts from spermine synthase-deficient hemizygous gyro male (Gy/Y) mice overproduce spermidine and exhibit increased resistance to oxidative stress but decreased resistance to UV irradiation.Biochem. J. 2000; 352: 381-387Crossref PubMed Google Scholar). Spermidine acts as the aminobutyl group donor for post-translational modification of a specific lysine residue of translation factor eIF5A by deoxyhypusine synthase. Subsequent hydroxylation by deoxyhypusine hydroxylase results in formation of Nϵ-(4-amino-2-hydroxybutyl)lysine (hypusine) (24.Park M.H. Cooper H.L. Folk J.E. Identification of hypusine, an unusual amino acid, in a protein from human lymphocytes and of spermidine as its biosynthetic precursor.Proc. Natl. Acad. Sci. U.S.A. 1981; 78: 2869-2873Crossref PubMed Scopus (188) Google Scholar, 25.Caraglia M. Park M.H. Wolff E.C. Marra M. Abbruzzese A. eIF5A isoforms and cancer: two brothers for two functions?.Amino Acids. 2013; 44: 103-109Crossref PubMed Scopus (72) Google Scholar). This modification is essential for eIF5A activity. The genes for eIF5A-1, deoxyhypusine synthase, and deoxyhypusine hydroxylase are essential for viability in mice (26.Nishimura K. Lee S.B. Park J.H. Park M.H. Essential role of eIF5A-1 and deoxyhypusine synthase in mouse embryonic development.Amino Acids. 2012; 42: 703-710Crossref PubMed Scopus (74) Google Scholar, 27.Pällmann N. Braig M. Sievert H. Preukschas M. Hermans-Borgmeyer I. Schweizer M. Nagel C.H. Neumann M. Wild P. Haralambieva E. Hagel C. Bokemeyer C. Hauber J. Balabanov S. Biological relevance and therapeutic potential of the hypusine modification system.J. Biol. Chem. 2015; 290: 18343-18360Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 28.Sievert H. Pällmann N. Miller K.K. Hermans-Borgmeyer I. Venz S. Sendoel A. Preukschas M. Schweizer M. Boettcher S. Janiesch P.C. Streichert T. Walther R. Hengartner M.O. Manz M.G. Brümmendorf T.H. et al.A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation.Dis. Model. Mech. 2014; 7: 963-976Crossref PubMed Scopus (41) Google Scholar). eIF5A may contribute to transcription, mRNA turnover, nucleocytoplasmic transport, and apoptosis (25.Caraglia M. Park M.H. Wolff E.C. Marra M. Abbruzzese A. eIF5A isoforms and cancer: two brothers for two functions?.Amino Acids. 2013; 44: 103-109Crossref PubMed Scopus (72) Google Scholar, 29.Mathews M.B. Hershey J.W. The translation factor eIF5A and human cancer.Biochim. Biophys. Acta. 2015; 1849: 836-844Crossref PubMed Scopus (109) Google Scholar), but its best understood function is to allow the translation of mRNAs encoding proteins containing polyproline tracts or triplets of PPX (where X may be Gly, Trp, Asp, or Asn) (30.Gutierrez E. Shin B.S. Woolstenhulme C.J. Kim J.R. Saini P. Buskirk A.R. Dever T.E. eIF5A promotes translation of polyproline motifs.Mol. Cell. 2013; 51: 35-45Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 31.Dever T.E. Gutierrez E. Shin B.S. The hypusine-containing translation factor eIF5A.Crit. Rev. Biochem. Mol. Biol. 2014; 49: 413-425Crossref PubMed Scopus (104) Google Scholar). Ribosomes arrest on such nascent polyproline stretches. The ribosome-bound hypusinylated eIF-5A reaches toward the peptidyltransferase center of the ribosome and stabilizes and orients the CCA end of the peptidyl-tRNA to allow synthesis through these regions (32.Schmidt C. Becker T. Heuer A. Braunger K. Shanmuganathan V. Pech M. Berninghausen O. Wilson D.N. Beckmann R. Structure of the hypusinylated eukaryotic translation factor eIF-5A bound to the ribosome.Nucleic Acids Res. 2016; 44: 1944-1951Crossref PubMed Scopus (72) Google Scholar). Proteins containing such proline repeats include proteins regulating key functions in growth and development including actin/cytoskeleton-associated functions, RNA splicing/turnover, DNA binding/transcription, and cell signaling (27.Pällmann N. Braig M. Sievert H. Preukschas M. Hermans-Borgmeyer I. Schweizer M. Nagel C.H. Neumann M. Wild P. Haralambieva E. Hagel C. Bokemeyer C. Hauber J. Balabanov S. Biological relevance and therapeutic potential of the hypusine modification system.J. Biol. Chem. 2015; 290: 18343-18360Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 33.Mandal A. Mandal S. Park M.H. Genome-wide analyses and functional classification of proline repeat-rich proteins: potential role of eIF5A in eukaryotic evolution.PLoS ONE. 2014; 9: e111800Crossref PubMed Scopus (51) Google Scholar). eIF5A is a relatively stable protein, but it can be acetylated either at Lys 47 (a residue essential for activity) by certain histone acetyltransferases or on the deoxyhypusine residue by SSAT (34.Lee S.B. Park J.H. Folk J.E. Deck J.A. Pegg A.E. Sokabe M. Fraser C.S. Park M.H. Inactivation of eukaryotic initiation factor 5A (eIF5A) by specific acetylation of its hypusine residue by spermidine/spermine acetyltransferase 1 (SSAT1).Biochem. J. 2011; 433: 205-213Crossref PubMed Scopus (25) Google Scholar), suggesting that its function may be regulated by acetylation/deacetylation. Vertebrates have a second gene encoding eIF5A2, which is not widely expressed and is not essential but is present in several cancers where it is associated with aggressive growth and a poor prognosis (27.Pällmann N. Braig M. Sievert H. Preukschas M. Hermans-Borgmeyer I. Schweizer M. Nagel C.H. Neumann M. Wild P. Haralambieva E. Hagel C. Bokemeyer C. Hauber J. Balabanov S. Biological relevance and therapeutic potential of the hypusine modification system.J. Biol. Chem. 2015; 290: 18343-18360Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 29.Mathews M.B. Hershey J.W. The translation factor eIF5A and human cancer.Biochim. Biophys. Acta. 2015; 1849: 836-844Crossref PubMed Scopus (109) Google Scholar). Prevention of hypusine formation in eIF5A2 inhibits tumor growth and reduces expression of the oncogenic tyrosine kinase PEAK1 (35.Fujimura K. Wright T. Strnadel J. Kaushal S. Metildi C. Lowy A.M. Bouvet M. Kelber J.A. Klemke R.L. A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer.Cancer Res. 2014; 74: 6671-6681Crossref PubMed Scopus (69) Google Scholar). Inhibitors of hypusine synthesis such as N1-guanyl-1,7-diaminoheptane (GC7) block growth in a similar way to DFMO (35.Fujimura K. Wright T. Strnadel J. Kaushal S. Metildi C. Lowy A.M. Bouvet M. Kelber J.A. Klemke R.L. A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer.Cancer Res. 2014; 74: 6671-6681Crossref PubMed Scopus (69) Google Scholar). Studies of the temporal effects in cells treated with both DFMO and N1-guanyl-1,7-diaminoheptane show a reduction of proliferation prior to the loss of hypusinated eIF5A, suggesting that spermidine is also required for other proliferative functions (36.Nishimura K. Murozumi K. Shirahata A. Park M.H. Kashiwagi K. Igarashi K. Independent roles of eIF5A and polyamines in cell proliferation.Biochem. J. 2005; 385: 779-785Crossref PubMed Scopus (114) Google Scholar). Interactions of polyamines with RNA can influence the content of individual proteins in multiple ways including alterations in ribosomal structure, facilitation of the formation of initiation complexes, and allowing readthrough of inefficient initiation complexes and enhancing frameshifting (3.Igarashi K. Kashiwagi K. Modulation of cellular function by polyamines.Int. J. Biochem. Cell Biol. 2010; 42: 39-51Crossref PubMed Scopus (590) Google Scholar, 37.Sakamoto A. Terui Y. Yoshida T. Yamamoto T. Suzuki H. Yamamoto K. Ishihama A. Igarashi K. Kashiwagi K. Three members of polyamine modulon under oxidative stress conditions: two transcription factors (SoxR and EmrR) and a glutathione synthetic enzyme (GshA).PLoS ONE. 2015; 10: e0124883Crossref PubMed Scopus (18) Google Scholar, 38.Ivanov I.P. Atkins J.F. Michael A.J. A profusion of upstream open reading frame mechanisms in polyamine-responsive translational regulation.Nucleic Acids Res. 2010; 38: 353-359Crossref PubMed Scopus (67) Google Scholar, 39.Yamashita T. Nishimura K. Saiki R. Okudaira H. Tome M. Higashi K. Nakamura M. Terui Y. Fujiwara K. Kashiwagi K. Igarashi K. Role of polyamines at the G1/S boundary and G2/M phase of the cell cycle.Int. J. Biochem. Cell Biol. 2013; 45: 1042-1050Crossref PubMed Scopus (31) Google Scholar). Polyamines can also affect protein content via direct and indirect effects on post-translational protein processing (40.Tolbert W.D. Zhang Y. Cottet S.E. Bennett E.M. Ekstrom J.L. Pegg A.E. Ealick S.E. Mechanism of human S-adenosylmethionine decarboxylase proenzyme processing as revealed by the structure of the S68A mutant.Biochemistry. 2003; 42: 2386-2395Crossref PubMed Scopus (37) Google Scholar, 41.Pegg A.E. 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Wang J.Y. Polyamines regulate intestinal epithelial restitution through TRPC1-mediated Ca2+ signaling by differentially modulating STIM1 and STIM2.Am. J. Physiol. Cell Physiol. 2012; 303: C308-317Crossref PubMed Scopus (58) Google Scholar, 45.Gao J.H. Guo L.J. Huang Z.Y. Rao J.N. Tang C.W. Roles of cellular polyamines in mucosal healing in the gastrointestinal tract.J. Physiol. Pharmacol. 2013; 64: 681-693PubMed Google Scholar, 46.Ray R.M. Guo H. Patel M. Jin S. Bhattacharya S. Johnson L.R. Role of myosin regulatory light chain and Rac1 in the migration of polyamine-depleted intestinal epithelial cells.Am. J. Physiol. Gastrointest. Liver Physiol. 2007; 292: G983-G995Crossref PubMed Scopus (20) Google Scholar). Polyamine content is critical for stem cell differentiation including adipogenesis (47.Ishii I. Ikeguchi Y. Mano H. Wada M. Pegg A.E. Shirahata A. Polyamine metabolism is involved in adipogenesis of 3T3-L1 cells.Amino Acids. 2012; 42: 619-626Crossref PubMed Scopus (31) Google Scholar, 48.Brenner S. Bercovich Z. Feiler Y. Keshet R. Kahana C. Dual regulatory role of polyamines in adipogenesis.J. Biol. Chem. 2015; 290: 27384-27392Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar), osteogenesis (49.Lee M.J. Chen Y. Huang Y.P. Hsu Y.C. Chiang L.H. Chen T.Y. Wang G.J. Exogenous polyamines promote osteogenic differentiation by reciprocally regulating osteogenic and adipogenic gene expression.J. Cell. Biochem. 2013; 114: 2718-2728Crossref PubMed Scopus (21) Google Scholar, 50.Yeon J.T. Ryu B.J. Choi S.W. Heo J.C. Kim K.J. Son Y.J. Kim S.H. Natural polyamines inhibit the migration of preosteoclasts by attenuating Ca2+-PYK2-Src-NFATc1 signaling pathways.Amino Acids. 2014; 46: 2605-2614Crossref PubMed Scopus (17) Google Scholar), and muscle development (51.Luchessi A.D. Cambiaghi T.D. Hirabara S.M. Lambertucci R.H. 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There is a very steep voltage dependence of the polyamine-mediated block, which is consistent with significant increases in excitability being associated with small changes in polyamine levels. Because spermine is more potent than spermidine (52.Lopatin A.N. Makhina E.N. Nichols C.G. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification.Nature. 1994; 372: 366-369Crossref PubMed Scopus (740) Google Scholar, 53.Stanfield P.R. Sutcliffe M.J. Spermine is fit to block inward rectifier (Kir) channels.J. Gen. Physiol. 2003; 122: 481-484Crossref PubMed Scopus (22) Google Scholar), a change in the ratio of polyamines may also bring about significant alterations in activity. Structural studies of the Kir1–7 subfamilies have shown that polyamines bind first to a “shallow” binding site at the cytoplasmic pore with weak voltage dependence and then migrate through a long pore to the deep position where they interact with an acidic residue described as the “rectification controller” to generate steep voltage dependence (54.Kurata H.T. Diraviyam K. Marton L.J. Nichols C.G. Blocker protection by short spermine analogs: refined mapping of the spermine binding site in a Kir channel.Biophys. J. 2008; 95: 3827-3839Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 55.Kurata H.T. Zhu E.A. Nichols C.G. Locale and chemistry of spermine binding in the archetypal inward rectifier Kir2.1.J. Gen. Physiol. 2010; 135: 495-508Crossref PubMed Scopus (20) Google Scholar, 56.Kurata H.T. Akrouh A. Li J.B. Marton L.J. Nichols C.G. Scanning the topography of polyamine blocker binding in an inwardly rectifying potassium channel.J. Biol. Chem. 2013; 288: 6591-6601Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar) (Fig. 2A). Variants corresponding to various SNPs of the KCNJ10 gene show differences in spermine binding and response (57.Méndez-González M.P. Kucheryavykh Y.V. Zayas-Santiago A. Vélez-Carrasco W. Maldonado-Martínez G. Cubano L.A. Nichols C.G. Skatchkov S.N. Eaton M.J. Novel KCNJ10 gene variations compromise function of inwardly rectifying potassium channel 4.1.J. Biol. Chem. 2016; 291: 7716-7726Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). The activities of gated ion channels that allow passage of cations through the cellular membrane and that respond to the binding of a ligand such as glutamate are involved in synaptic transmission and synaptic plasticity underlying learning and memory. There are three groups of these receptors each with multiple members based on their modifying agents: NMDA; AMPA; and kainate. The activities of some members of all three groups can be influenced by polyamines (3.Igarashi K. Kashiwagi K. Modulation of cellular function by polyamines.Int. J. Biochem. Cell Biol. 2010; 42: 39-51Crossref PubMed Scopus (590) Google Scholar, 58.Williams K. Romano C. Molinoff P.B. Effects of polyamines on the binding of [3H]MK-801 to the N-methyl-d-aspartate receptor: pharmacological evidence for the existence of a polyamine recognition site.Mol. Pharmacol. 1989; 36: 575-581PubMed Google Scholar, 59.Bowie D. Mayer M.L. Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block.Neuron. 1995; 15: 453-462Abstract Full Text PDF PubMed Scopus (483) Google Scholar, 60.Williams K. Modulation and block of ion channels: a new biology of polyamines.Cell. Signal. 1997; 9: 1-13Crossref PubMed Scopus (214) Google Scholar). These include some NMDA receptors that act as both ligand-gated and voltage-dependent channels and control synaptic plasticity (3.Igarashi K. Kashiwagi K. Modulation of cellular function by polyamines.Int. J. Biochem. Cell Biol. 2010; 42: 39-51Crossref PubMed Scopus (590) Google Scholar, 58.Williams K. Romano C. Molinoff P.B. Effects of polyamines on the binding of [3H]MK-801 to the N-methyl-d-aspartate receptor: pharmacological evidence for the existence of a polyamine recognition site.Mol. Pharmacol. 1989; 36: 575-581PubMed Google Scholar, 60.Williams K. Modulation and block of ion channels: a new biology of polyamines.Cell. Signal. 1997; 9: 1-13Crossref PubMed Scopus (214) Google Scholar). Spermine is more potent than spermidine, and a wide variety of longer synthetic polyamines have been shown to have potent pharmacological effects. The effects of polyamines involve at least two sites and can lead to both stimulation and a weak voltage-dependent inhibition representing an open channel block. This complexity of effects reflects both the varied subunit composition of the receptors and their stimulatory agent and the presence of multiple sites at which polyamines can bind (61.Han X. Tomitori H. Mizuno S. Higashi K. Füll C. Fukiwake T. Terui Y. Leewanich P. Nishimura K. Toida T. Williams K. Kashiwagi K. Igarashi K. Binding of spermine and ifenprodil to a purified, soluble regulatory domain of the N-methyl-d-aspartate receptor.J. Neuroche" @default.
• W2412031353 created "2016-06-24" @default.
• W2412031353 creator A5040141654 @default.
• W2412031353 date "2016-07-01" @default.
• W2412031353 modified "2023-10-17" @default.
• W2412031353 title "Functions of Polyamines in Mammals" @default.
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