title: Hemopressin and other bioactive peptides from cytosolic proteins: are these non-classical neuropeptides?
abstract: Peptides perform many roles in cell-cell signaling; examples include neuropeptides, hormones, and growth factors. Although the vast majority of known neuropeptides are produced in the secretory pathway, a number of bioactive peptides are derived from cytosolic proteins. For example, the hemopressins are a family of peptides derived from alpha and beta hemoglobin which bind to the CB1 cannabinoid receptor, functioning as agonists or antagonists/inverse agonists depending on the size of the peptide. However, the finding that peptides derived from cytosolic proteins can affect receptors does not prove that these peptides are true endogenous signaling molecules. In order for the hemopressins and other peptides derived from cytosolic proteins to be considered neuropeptide-like signaling molecules, they must be synthesized in brain, they must be secreted in levels sufficient to produce effects, and either their synthesis or secretion should be regulated. If these criteria are met, we propose the name "non-classical neuropeptide" for this category of cytosolic bioactive peptide. This would be analogous to the non-classical neurotransmitters, such as nitric oxide and anandamide, which are not stored in secretory vesicles and released upon stimulation but are synthesized upon stimulation and constitutively released. We review some examples of cytosolic peptides from various protein precursors, describe potential mechanisms of their biosynthesis and secretion, and discuss the possibility that these peptides are signaling molecules in the brain, focusing on the criteria that these peptides would have to fill in order to be considered non-classical neuropeptides.
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Gelman
authors.forename: Lloyd D
authors.initials: LD
authors.lastname: Fricker
mesh_terms: D003600:Cytosol / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*
chemical_list: D006454:Hemoglobins; D009479:Neuropeptides; D010446:Peptide Fragments; D011506:Proteins; C473218:hemopressin
references.citation: Peptides. 2005 Mar;26(3):431-6
references.pmid: 15652650
references.citation: Dev Comp Immunol. 2008;32(11):1301-12
references.pmid: 18538841
references.citation: Nat Rev Mol Cell Biol. 2004 Nov;5(11):897-907
references.pmid: 15520809
references.citation: J Biol Chem. 2000 Sep 1;275(35):27447-56
references.pmid: 10862611
references.citation: J Neurosci Res. 2007 Oct;85(13):2898-908
references.pmid: 17628502
references.citation: Arthritis Rheum. 1984 May;27(5):509-15
references.pmid: 6721883
references.citation: Science. 1985 Jul 12;229(4709):179-82
references.pmid: 3892688
references.citation: Nat Rev Mol Cell Biol. 2009 Feb;10(2):148-55
references.pmid: 19122676
references.citation: J Biol Chem. 2006 Nov 10;281(45):34277-87
references.pmid: 16968707
references.citation: J Biol Chem. 2004 Feb 20;279(8):6244-51
references.pmid: 14645213
references.citation: Nature. 1979 Nov 22;282(5737):410-2
references.pmid: 228202
references.citation: Neurobiol Aging. 2006 Apr;27(4):614-23
references.pmid: 15941609
references.citation: Br J Pharmacol. 2008 Sep;155(2):152-69
references.pmid: 18641677
references.citation: Peptides. 1989 Jul-Aug;10(4):747-51
references.pmid: 2587417
references.citation: J Cell Sci. 2002 Sep 15;115(Pt 18):3619-31
references.pmid: 12186948
references.citation: Int J Biochem Cell Biol. 1997 Nov;29(11):1219-23
references.pmid: 9451817
references.citation: AAPS J. 2005 Oct 05;7(2):E449-55
references.pmid: 16353923
references.citation: J Immunol. 2009 Apr 15;182(8):5072-80
references.pmid: 19342687
references.citation: J Biol Chem. 2003 Mar 7;278(10):7751-4
references.pmid: 12551931
references.citation: Annu Rev Cell Dev Biol. 1995;11:417-40
references.pmid: 8689564
references.citation: Crit Rev Biochem Mol Biol. 2007 May-Jun;42(3):221-42
references.pmid: 17562452
references.citation: J Comp Neurol. 2009 Aug 10;515(5):538-47
references.pmid: 19479992
references.citation: Trends Pharmacol Sci. 2008 Jan;29(1):22-8
references.pmid: 18037508
references.citation: Physiol Rev. 2003 Jul;83(3):731-801
references.pmid: 12843408
references.citation: Peptides. 1998;19(4):759-66
references.pmid: 9622033
references.citation: P R Health Sci J. 1996 Sep;15(3):179-86
references.pmid: 8994282
references.citation: J Immunol. 2001 Dec 1;167(11):6441-6
references.pmid: 11714810
references.citation: J Biol Chem. 1988 Apr 5;263(10):4869-75
references.pmid: 3127394
references.citation: Biochem Biophys Res Commun. 1992 Apr 30;184(2):1060-6
references.pmid: 1575724
references.citation: Mol Vis. 2003 Aug 22;9:360-96
references.pmid: 12942050
references.citation: Curr Med Chem. 2002 Jun;9(11):1107-19
references.pmid: 12052175
references.citation: J Biol Chem. 1997 Apr 11;272(15):9677-82
references.pmid: 9092497
references.citation: Eur J Pharmacol. 1986 Jun 17;125(2):309-10
references.pmid: 3743640
references.citation: Hum Reprod. 2008 Mar;23(3):635-41
references.pmid: 18216035
references.citation: Biopolymers. 1997;43(2):147-56
references.pmid: 9216251
references.citation: FEBS Lett. 1992 Mar 24;299(1):75-9
references.pmid: 1544478
references.citation: J Pharmacol Exp Ther. 2003 Apr;305(1):205-11
references.pmid: 12649370
references.citation: J Proteome Res. 2007 Mar;6(3):1083-92
references.pmid: 17284061
references.citation: J Biol Chem. 1999 Jul 23;274(30):20745-8
references.pmid: 10409610
references.citation: Nat Rev Cancer. 2006 Oct;6(10):764-75
references.pmid: 16990854
references.citation: J Am Soc Nephrol. 2008 Aug;19(8):1500-8
references.pmid: 18448584
references.citation: ACS Chem Neurosci. 2010 Jan 8;1(4):306-314
references.pmid: 20495672
references.citation: J Mol Neurosci. 2010 May;41(1):36-47
references.pmid: 19705086
references.citation: J Comp Neurol. 2001 Oct 1;438(4):399-410
references.pmid: 11559896
references.citation: Ernst Schering Found Symp Proc. 2008;(1):17-40
references.pmid: 19198062
references.citation: FEBS Lett. 2003 Sep 11;551(1-3):78-86
references.pmid: 12965208
references.citation: Bioessays. 1992 Aug;14(8):549-56
references.pmid: 1365908
references.citation: J Proteome Res. 2007 Dec;6(12):4667-76
references.pmid: 17979226
references.citation: Cell Death Differ. 2008 Mar;15(3):453-60
references.pmid: 18174901
references.citation: Protein Pept Lett. 2004 Oct;11(5):415-21
references.pmid: 15544562
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15454-9
references.pmid: 19717439
references.citation: Biopolymers. 1997;43(2):171-88
references.pmid: 9216253
references.citation: Biochemistry. 1997 Jan 7;36(1):57-65
references.pmid: 8993318
references.citation: J Med Chem. 2007 Jun 28;50(13):3070-6
references.pmid: 17550241
references.citation: Life Sci. 1991;49(5):325-44
references.pmid: 1649940
references.citation: Science. 2002 Jun 21;296(5576):2215-8
references.pmid: 12077416
references.citation: FEBS J. 2007 Jan;274(2):474-84
references.pmid: 17229152
references.citation: Peptides. 2005 Aug;26(8):1317-22
references.pmid: 16042973
references.citation: J Pharmacol Exp Ther. 2006 Jul;318(1):336-44
references.pmid: 16608915
references.citation: Biochim Biophys Acta. 2007 Sep;1773(9):1389-97
references.pmid: 17582523
references.citation: Acta Biochim Biophys Sin (Shanghai). 2004 Dec;36(12):787-92
references.pmid: 15592644
references.citation: J Neurochem. 2010 May;113(4):871-80
references.pmid: 20202081
references.citation: Neurodegener Dis. 2006;3(4-5):275-83
references.pmid: 17047368
references.citation: Endocr Rev. 2001 Apr;22(2):184-204
references.pmid: 11294823
references.citation: J Biol Chem. 2007 Jun 22;282(25):18573-18583
references.pmid: 17442669
references.citation: Mol Neurobiol. 2008 Aug;38(1):78-100
references.pmid: 18686046
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6643-7
references.pmid: 10359765
references.citation: Ann N Y Acad Sci. 2007 Sep;1112:326-38
references.pmid: 17495242
references.citation: Biopolymers. 2007;88(2):190-8
references.pmid: 17245751
references.citation: Biol Chem. 2008 Mar;389(3):203-9
references.pmid: 18208355
references.citation: J Immunol. 2007 Aug 1;179(3):1913-25
references.pmid: 17641058
references.citation: Cancer Cell. 2004 May;5(5):409-10
references.pmid: 15144947
references.citation: J Biol Chem. 1997 Oct 3;272(40):25200-9
references.pmid: 9312134
references.citation: J Biol Chem. 2004 Mar 26;279(13):13054-64
references.pmid: 14724289
references.citation: Int J Immunopharmacol. 1997 Jun;19(6):323-32
references.pmid: 9467751
references.citation: J Biol Chem. 2003 Feb 7;278(6):3671-8
references.pmid: 12446702
references.citation: Proc Natl Acad Sci U S A. 1977 Feb;74(2):725-9
references.pmid: 265536
references.citation: J Neurochem. 1989 Oct;53(4):1276-84
references.pmid: 2769267
references.citation: Neurochem Res. 1990 Feb;15(2):161-8
references.pmid: 2159121
references.citation: Pharmacotherapy. 2006 Dec;26(12 Pt 2):218S-221S
references.pmid: 17125448
references.citation: Biochem Soc Symp. 2003;(70):243-51
references.pmid: 14587297
references.citation: Peptides. 2006 Nov;27(11):2957-66
references.pmid: 16904236
references.citation: Annu Rev Biochem. 1999;68:1015-68
references.pmid: 10872471
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20588-93
references.pmid: 18077343
references.citation: J Biol Chem. 2004 Aug 13;279(33):34776-84
references.pmid: 15184381
references.citation: J Biol Chem. 2006 Mar 3;281(9):5668-76
references.pmid: 16407281
references.citation: Biochem Biophys Res Commun. 2007 Oct 26;362(3):587-93
references.pmid: 17716628
references.citation: Curr Opin Neurobiol. 2001 Oct;11(5):585-90
references.pmid: 11595492
references.citation: Endocr Rev. 1998 Oct;19(5):608-24
references.pmid: 9793760
references.citation: FASEB J. 2009 Sep;23(9):3020-9
references.pmid: 19380512
references.citation: Proteomics. 2006 Nov;6(21):5805-14
references.pmid: 17001601
references.citation: Mol Biol Cell. 1999 May;10(5):1463-75
references.pmid: 10233156
references.citation: J Biol Chem. 2008 Nov 7;283(45):30596-605
references.pmid: 18768476
references.citation: J Biol Chem. 2003 Mar 7;278(10):8547-55
references.pmid: 12500972
references.citation: Biochem Biophys Res Commun. 1992 Sep 16;187(2):751-9
references.pmid: 1530632
references.citation: J Mol Neurosci. 2002 Jun;18(3):203-10
references.pmid: 12059038
references.citation: Cell. 2004 Jan 23;116(2 Suppl):S53-6, 1 p following S59
references.pmid: 15055582
references.citation: J Biol Chem. 1982 Jan 25;257(2):1000-6
references.pmid: 7054160
references.citation: J Biol Chem. 2001 Jan 5;276(1):535-40
references.pmid: 11034991
references.citation: Peptides. 2006 Sep;27(9):2284-8
references.pmid: 16713023
references.citation: Mem Inst Oswaldo Cruz. 2005 Mar;100 Suppl 1:105-6
references.pmid: 15962106
references.citation: Proteomics. 2002 Apr;2(4):447-54
references.pmid: 12164705
references.citation: J Neurochem. 2004 Nov;91(4):769-77
references.pmid: 15525330
references.citation: Proc Natl Acad Sci U S A. 1986 Feb;83(3):827-31
references.pmid: 3456171
references.citation: Cell. 1998 Jul 24;94(2):161-70
references.pmid: 9695945
references.citation: Mol Immunol. 2009 Feb;46(5):784-92
references.pmid: 18976813
references.citation: J Biol Chem. 2005 Dec 9;280(49):40632-41
references.pmid: 16216885
references.citation: FEBS Lett. 1991 Aug 5;287(1-2):39-41
references.pmid: 1652464
references.citation: Biopolymers. 1997;43(2):75-98
references.pmid: 9216245
references.citation: Int J Pept Protein Res. 1992 Jun;39(6):477-84
references.pmid: 1356941
references.citation: Science. 1985 Oct 25;230(4724):400-7
references.pmid: 4048938
references.citation: Prog Neurobiol. 2000 Jan;60(1):37-83
references.pmid: 10622376
references.citation: Int J Biochem Cell Biol. 2001 Mar;33(3):205-20
references.pmid: 11311852
references.citation: Cell. 2000 Oct 27;103(3):375-86
references.pmid: 11081625
references.citation: Trends Mol Med. 2005 Sep;11(9):421-9
references.pmid: 16099219
references.citation: FEBS Lett. 1996 Mar 11;382(1-2):37-42
references.pmid: 8612760
references.citation: Annu Rev Genet. 2008;42:191-210
references.pmid: 18605900
references.citation: FEBS Lett. 1997 Sep 1;414(1):125-8
references.pmid: 9305745
references.citation: Biochim Biophys Acta. 2000 Mar 7;1477(1-2):98-111
references.pmid: 10708852
references.citation: Biochem Biophys Res Commun. 2005 Aug 12;333(4):1348-52
references.pmid: 15979582
references.citation: Brain Res. 1992 Feb 14;572(1-2):164-71
references.pmid: 1611510
references.citation: Genome Res. 2007 Nov;17(11):1634-46
references.pmid: 17938163
references.citation: Life Sci. 1982 Oct 18-25;31(16-17):1733-6
references.pmid: 7154833
references.citation: Physiol Rev. 2002 Apr;82(2):331-71
references.pmid: 11917092
references.citation: Annu Rev Physiol. 1988;50:309-21
references.pmid: 2897826
references.citation: J Cell Biol. 2005 Oct 24;171(2):373-81
references.pmid: 16247033
references.citation: J Mol Endocrinol. 2001 Jun;26(3):155-64
references.pmid: 11432370