title: Issues about the physiological functions of prolyl oligopeptidase based on its discordant spatial association with substrates and inconsistencies among mRNA, protein levels, and enzymatic activity.
abstract: Prolyl oligopeptidase (POP) is a serine endopeptidase that hydrolyses proline-containing peptides shorter than 30 amino acids. POP may be associated with cognitive functions, possibly via the cleavage of neuropeptides. Recent studies have also suggested novel non-hydrolytic and non-catalytic functions for POP. Moreover, POP has also been proposed as a regulator of inositol 1,4,5-triphosphate signaling and several other functions such as cell proliferation and differentiation, as well as signal transduction in the central nervous system, and it is suspected to be involved in pathological conditions such as Parkinson's and Alzheimer's diseases and cancer. POP inhibitors have been developed to restore the depleted neuropeptide levels encountered in aging or in neurodegenerative disorders. These compounds have shown some antiamnesic effects in animal models. However, the mechanisms of these hypothesized actions are still far from clear. Moreover, the physiological role of POP has remained unknown, and a lack of basic studies, including its distribution, is obvious. The aim of this review is to gather information about POP and to propose some novel roles for this enzyme based on its distribution and its discordant spatial association with its best known substrates.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland. Timo.Myohanen@uku.fi
authors.forename: Timo T
authors.initials: TT
authors.lastname: Myöhänen
authors.forename: J Arturo
authors.initials: JA
authors.lastname: García-Horsman
authors.forename: Jofre
authors.initials: J
authors.lastname: Tenorio-Laranga
authors.forename: Pekka T
authors.initials: PT
authors.lastname: Männistö
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D002384:Catalysis; D002454:Cell Differentiation; D049109:Cell Proliferation; D006801:Humans; D009043:Motor Activity; D018377:Neurotransmitter Agents / Q000378:metabolism; D009928:Organ Specificity; D000085822:Prolyl Oligopeptidases; D012333:RNA, Messenger / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013379:Substrate Specificity
chemical_list: D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases
references.citation: Nat Chem Biol. 2007 Oct;3(10):619-29
references.pmid: 17876319
references.citation: Drug News Perspect. 2007 Jun;20(5):293-305
references.pmid: 17878957
references.citation: J Proteome Res. 2008 Aug;7(8):3447-60
references.pmid: 18563927
references.citation: Neurochem Int. 2005 Sep;47(4):248-59
references.pmid: 15985312
references.citation: Eur J Clin Chem Clin Biochem. 1996 Jan;34(1):17-22
references.pmid: 8704029
references.citation: Biochim Biophys Acta. 1976 Jan 23;422(1):138-58
references.pmid: 2300
references.citation: Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11675-80
references.pmid: 9326669
references.citation: J Pharmacol Exp Ther. 1995 Sep;274(3):1370-8
references.pmid: 7562510
references.citation: Peptides. 2008 Sep;29(9):1472-8
references.pmid: 18571285
references.citation: J Neurochem. 1986 Apr;46(4):1304-7
references.pmid: 3512777
references.citation: Braz J Med Biol Res. 1994 Dec;27(12):2821-30
references.pmid: 7550002
references.citation: Neurosci Res. 2007 Mar;57(3):362-71
references.pmid: 17134780
references.citation: J Biochem. 1994 Mar;115(3):449-53
references.pmid: 8056756
references.citation: Acta Endocrinol (Copenh). 1992 Sep;127(3):262-6
references.pmid: 1357903
references.citation: Neurosci Lett. 1996 Aug 23;214(2-3):151-4
references.pmid: 8878106
references.citation: Insect Biochem Mol Biol. 1997 Apr;27(4):337-43
references.pmid: 9134713
references.citation: Methods Enzymol. 1994;244:188-200
references.pmid: 7845207
references.citation: J Gerontol A Biol Sci Med Sci. 2003 Sep;58(9):B792-7
references.pmid: 14528034
references.citation: Mol Cell Neurosci. 2009 Jul;41(3):373-82
references.pmid: 19332125
references.citation: Regul Pept. 1994 Mar 17;50(3):235-45
references.pmid: 8016408
references.citation: Prog Brain Res. 2007;160:273-84
references.pmid: 17499120
references.citation: J Biol Chem. 1999 Aug 20;274(34):24047-53
references.pmid: 10446174
references.citation: Neuropeptides. 2000 Oct;34(5):272-80
references.pmid: 11049731
references.citation: CNS Drug Rev. 2002 Spring;8(1):31-52
references.pmid: 12070525
references.citation: Eur J Biochem. 1995 Jan 15;227(1-2):277-83
references.pmid: 7851396
references.citation: Learn Mem. 2005 Nov-Dec;12(6):594-600
references.pmid: 16287718
references.citation: Eur J Biochem. 1998 Feb 15;252(1):178-83
references.pmid: 9523728
references.citation: Bipolar Disord. 2004 Apr;6(2):156-61
references.pmid: 15005755
references.citation: Protein Eng Des Sel. 2008 Feb;21(2):83-9
references.pmid: 18175776
references.citation: J Cell Biol. 2000 Jun 26;149(7):1455-72
references.pmid: 10871285
references.citation: Science. 1971 Aug 27;173(3999):827-9
references.pmid: 5572174
references.citation: Nature. 1993 Jan 7;361(6407):31-9
references.pmid: 8421494
references.citation: Brain Res. 2004 Feb 27;999(1):20-8
references.pmid: 14746918
references.citation: Toxicol In Vitro. 2006 Dec;20(8):1446-54
references.pmid: 16942854
references.citation: J Neurochem. 1982 Apr;38(4):1151-4
references.pmid: 7038048
references.citation: Neuroscience. 2004;123(1):5-9
references.pmid: 14667436
references.citation: J Biochem. 1997 Jun;121(6):1176-81
references.pmid: 9354394
references.citation: Pharmacol Biochem Behav. 1997 Mar;56(3):427-34
references.pmid: 9077579
references.citation: Eur J Biochem. 2002 Dec;269(23):5813-20
references.pmid: 12444969
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D320-5
references.pmid: 17991683
references.citation: Am Heart J. 2003 Jul;146(1):9-18
references.pmid: 12851603
references.citation: Clin Chim Acta. 1996 May 30;249(1-2):129-39
references.pmid: 8737597
references.citation: J Pharmacobiodyn. 1987 Dec;10(12):730-5
references.pmid: 3330562
references.citation: J Neurochem. 1995 Jul;65(1):234-40
references.pmid: 7540663
references.citation: J Biochem. 1994 Apr;115(4):724-9
references.pmid: 8089089
references.citation: Neurosci Res. 2007 Feb;57(2):248-58
references.pmid: 17141345
references.citation: FEBS J. 2008 Sep;275(17):4415-27
references.pmid: 18657187
references.citation: Protein Eng Des Sel. 2004 Jun;17(6):527-36
references.pmid: 15314210
references.citation: Endocrinology. 1989 Sep;125(3):1492-7
references.pmid: 2503371
references.citation: Learn Mem. 1998 Sep-Oct;5(4-5):317-30
references.pmid: 10454357
references.citation: Mol Pharmacol. 2009 Jan;75(1):218-26
references.pmid: 18927208
references.citation: Physiol Res. 1992;41(6):475-8
references.pmid: 1299333
references.citation: Prog Neurobiol. 1997 Dec;53(6):627-86
references.pmid: 9447616
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jul;29(6):1029-37
references.pmid: 15950352
references.citation: Eur J Biochem. 2004 Jul;271(13):2705-15
references.pmid: 15206935
references.citation: Brain Res. 1984 Dec 24;324(2):261-70
references.pmid: 6085024
references.citation: Mol Cell Neurosci. 2005 Jun;29(2):155-61
references.pmid: 15911340
references.citation: Chem Pharm Bull (Tokyo). 1985 Jun;33(6):24445-51
references.pmid: 3905033
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12880-4
references.pmid: 11070096
references.citation: Biochem Pharmacol. 2003 Jul 15;66(2):179-89
references.pmid: 12826261
references.citation: Gene. 1994 Nov 18;149(2):363-6
references.pmid: 7959018
references.citation: J Biochem. 1998 Mar;123(3):540-5
references.pmid: 9538240
references.citation: Epilepsy Res. 1996 Feb;23(1):37-53
references.pmid: 8925802
references.citation: Brain Res. 1988 Apr 12;446(1):173-7
references.pmid: 2453256
references.citation: Biochem Biophys Res Commun. 1997 Jun 27;235(3):641-5
references.pmid: 9207212
references.citation: J Pharmacol Exp Ther. 1997 Oct;283(1):328-35
references.pmid: 9336340
references.citation: Biochim Biophys Acta. 1997 Dec 5;1343(2):160-86
references.pmid: 9434107
references.citation: Experientia. 1990 Jan 15;46(1):94-7
references.pmid: 1688809
references.citation: Glia. 2008 Apr 15;56(6):675-85
references.pmid: 18293395
references.citation: Anticancer Res. 2008 Sep-Oct;28(5A):2813-7
references.pmid: 19035315
references.citation: Neurosci Lett. 2009 Jan 30;450(2):201-5
references.pmid: 19041368
references.citation: J Pharmacobiodyn. 1982 Sep;5(9):734-40
references.pmid: 6185666
references.citation: Eur J Pharmacol. 1996 Jun 3;305(1-3):31-8
references.pmid: 8813528
references.citation: Brain Res. 1990 Sep 10;527(1):159-62
references.pmid: 2282478
references.citation: Endocrinology. 2004 Jul;145(7):3095-100
references.pmid: 15117874
references.citation: J Neurocytol. 2002 Mar-Jun;31(3-5):299-316
references.pmid: 12815249
references.citation: Neuroscience. 1990;39(1):33-58
references.pmid: 1708467
references.citation: J Neuroendocrinol. 2005 May;17(5):306-13
references.pmid: 15869566
references.citation: Neuroscience. 1982 Mar;7(3):639-45
references.pmid: 6175921
references.citation: J Comp Neurol. 2008 Apr 10;507(5):1694-708
references.pmid: 18253937
references.citation: Biochem Biophys Res Commun. 2004 Mar 26;316(1):78-84
references.pmid: 15003514
references.citation: Clin Chim Acta. 2007 Feb;377(1-2):50-61
references.pmid: 17034776
references.citation: Basic Clin Pharmacol Toxicol. 2007 Feb;100(2):132-8
references.pmid: 17244263
references.citation: Methods Enzymol. 1994;244:19-61
references.pmid: 7845208
references.citation: Endocr Rev. 1999 Oct;20(5):599-648
references.pmid: 10529897
references.citation: Int J Biochem. 1985;17(4):521-4
references.pmid: 3891453
references.citation: J Comp Physiol B. 2005 Aug;175(6):433-44
references.pmid: 16044310
references.citation: J Comp Neurol. 1998 Dec 14;402(2):181-96
references.pmid: 9845242
references.citation: Neurology. 1979 Jan;29(1):96-9
references.pmid: 370687
references.citation: J Neurocytol. 2002 Mar-Jun;31(3-5):277-87
references.pmid: 12815247
references.citation: Am J Physiol. 1990 Dec;259(6 Pt 1):E787-91
references.pmid: 1979716
references.citation: Behav Brain Res. 1995 Jan 23;66(1-2):117-27
references.pmid: 7538769
references.citation: Mol Cell Biochem. 1980 Nov 20;32(3):117-21
references.pmid: 7007867
references.citation: J Neural Transm Suppl. 1987;24:163-74
references.pmid: 2445913
references.citation: Biochim Biophys Acta. 1994 Apr 21;1199(3):279-84
references.pmid: 8161566
references.citation: Pharmacol Biochem Behav. 1998 Feb;59(2):361-8
references.pmid: 9476982
references.citation: J Neurochem. 2003 Mar;84(5):919-29
references.pmid: 12603817
references.citation: Regul Pept. 2001 Sep 15;101(1-3):141-7
references.pmid: 11495689
references.citation: Peptides. 2005 Dec;26(12):2536-46
references.pmid: 15996789
references.citation: Peptides. 2006 Jun;27(6):1561-9
references.pmid: 16406204
references.citation: Int J Biochem Cell Biol. 1996 Apr;28(4):441-9
references.pmid: 9026355
references.citation: Neuroscience. 1979;4(1):1-30
references.pmid: 32499
references.citation: J Biol Chem. 1990 Dec 15;265(35):21448-53
references.pmid: 2254307
references.citation: J Neurochem. 1991 Jan;56(1):113-8
references.pmid: 1846169
references.citation: Neuroscience. 2008 Jun 2;153(4):1177-89
references.pmid: 18455882
references.citation: J Mol Endocrinol. 2003 Apr;30(2):87-97
references.pmid: 12683933
references.citation: J Biochem. 1981 Aug;90(2):325-34
references.pmid: 7028730
references.citation: Cell. 1998 Jul 24;94(2):161-70
references.pmid: 9695945
references.citation: Eur J Pharmacol. 1993 Mar 16;233(1):21-8
references.pmid: 8472746
references.citation: J Mol Biol. 2004 Jul 9;340(3):627-37
references.pmid: 15210359
references.citation: Front Neuroendocrinol. 2002 Oct;23(4):317-41
references.pmid: 12381329
references.citation: J Biol Chem. 1995 Jun 9;270(23):13892-8
references.pmid: 7775448
references.citation: J Comp Neurol. 1994 Sep 8;347(2):249-74
references.pmid: 7814667
references.citation: Int J Biochem Cell Biol. 1998 Jan;30(1):99-114
references.pmid: 9597757
references.citation: Behav Brain Res. 1999 Feb 15;99(1):17-25
references.pmid: 10512568
references.citation: J Neurochem. 1980 Sep;35(3):527-35
references.pmid: 6161226
references.citation: Trends Pharmacol Sci. 2000 Feb;21(2):61-4
references.pmid: 10664610
references.citation: Neurochem Res. 2005 Jun-Jul;30(6-7):695-702
references.pmid: 16187206
references.citation: Regul Pept. 2007 Mar 1;139(1-3):52-8
references.pmid: 17123646
references.citation: J Neurochem. 2005 Aug;94(4):970-9
references.pmid: 16092940
references.citation: Brain Res. 1994 Sep 12;656(2):229-35
references.pmid: 7529639
references.citation: J Comp Neurol. 2004 Mar 29;471(2):128-43
references.pmid: 14986307
references.citation: Mol Cell Biochem. 1991 Jul 24;106(1):15-24
references.pmid: 1681421
references.citation: Lancet Neurol. 2003 Aug;2(8):463-72
references.pmid: 12878434
references.citation: Biochem Med Metab Biol. 1991 Apr;45(2):154-60
references.pmid: 1679339
references.citation: Histochem Cell Biol. 2008 Nov;130(5):993-1003
references.pmid: 18618130
references.citation: Neurochem Int. 2002 Apr;40(4):337-45
references.pmid: 11792464
references.citation: Neuroscience. 2008 Oct 15;156(3):580-5
references.pmid: 18718510
references.citation: Horm Metab Res. 1992 Mar;24(3):110-4
references.pmid: 1349555
references.citation: J Neurophysiol. 2000 Aug;84(2):1093-7
references.pmid: 10938331
references.citation: Neurosci Lett. 1996 Jul 26;213(1):29-32
references.pmid: 8844705
references.citation: Int J Biochem Cell Biol. 2001 Jun;33(6):555-76
references.pmid: 11378438
references.citation: EMBO J. 2003 Jun 16;22(12):3004-14
references.pmid: 12805215
references.citation: Hypertension. 2004 May;43(5):1140-5
references.pmid: 15037553
references.citation: Zoolog Sci. 2002 Jan;19(1):93-102
references.pmid: 12025410
references.citation: Nature. 2002 May 16;417(6886):292-5
references.pmid: 12015604
references.citation: Annu Rev Neurosci. 1992;15:403-42
references.pmid: 1575449
references.citation: Neurochem Res. 2007 Aug;32(8):1365-74
references.pmid: 17401647
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4465-70
references.pmid: 11904358
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1930-4
references.pmid: 11172053
references.citation: Neuropeptides. 2007 Feb;41(1):1-24
references.pmid: 17196652
references.citation: Bull Exp Biol Med. 2006 Nov;142(5):554-6
references.pmid: 17415460
references.citation: Adv Exp Med Biol. 2006;575:103-8
references.pmid: 16700513
references.citation: Peptides. 1990 Mar-Apr;11(2):375-80
references.pmid: 2162536
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):14009-14
references.pmid: 9391143
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1996 Feb;353(3):355-62
references.pmid: 8692293