title: Human RFamide-related peptide-1 diminishes cellular and integrated cardiac contractile performance.
abstract: Peptides influence cardiac dysfunction; however, peptidergic modulation of contractile performance remains relatively uncharacterized. We identified a novel human peptide that modulates mammalian contractile performance. Members of the FMRFamide-related peptide (FaRP) family contain a C-terminal RFamide but structurally variant N-terminal extension. We report human RFamide-related peptide-1 (hRFRP-1) and rat RFRP-1 rapidly and reversibly decreased shortening and relaxation in isolated mammalian cardiac myocytes in a dose dependent manner. The mammalian FaRP, 26RFa, structurally related to RFRP-1 by only an RFamide did not influence myocyte contractile function. The protein kinase C (PKC) inhibitor bisindolylmaleimide-1 blocked hRFRP-1 activity. Pretreatment with pertussis toxin (PTX) did not diminish hRFRP-1 influence on contractile function. In addition, intravenous injection of hRFRP-1 in mice decreased heart rate, stroke volume, ejection fraction, and cardiac output. Collectively these findings are consistent with the conclusion RFRP-1 is an endogenous signaling molecule that activates PKC and acts through a PTX-insensitive pathway to modulate cardiac contractile function. Taken together these negative chronotropic, inotropic, and lusitropic effects of hRFRP-1 are significant; they suggest direct acute cellular and organ-level responses in mammalian heart. This is the first known study to identify a mammalian FaRP with cardio-depressant effects, opening a new area of research on peptidergic modulation of contractile performance. The high degree of RFRP structure conservation from amphibians to mammals, and similarity to invertebrate cardioinhibitory peptides suggests RFRP-1 is involved in important physiological functions. Elucidation of mechanisms involved in hRFRP-1 synthesis, release, and signaling may aid the development of strategies to prevent or attenuate cardiac dysfunction.
authors.affiliation: Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor, MI 48109, USA. nicholsr@umich.edu
authors.forename: R
authors.initials: R
authors.lastname: Nichols
authors.forename: L A
authors.initials: LA
authors.lastname: Demers
authors.forename: B M
authors.initials: BM
authors.lastname: Larsen
authors.forename: D
authors.initials: D
authors.lastname: Robinson
authors.forename: K
authors.initials: K
authors.lastname: Converso
authors.forename: M W
authors.initials: MW
authors.lastname: Russell
authors.forename: M V
authors.initials: MV
authors.lastname: Westfall
mesh_terms: D000818:Animals; D003864:Depression, Chemical; D006801:Humans; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000494:pharmacology* / Q000502:physiology*; D011493:Protein Kinase C; D011817:Rabbits; D051381:Rats
chemical_list: D009479:Neuropeptides; C416987:RFamide peptide; D011493:Protein Kinase C
references.citation: J Exp Biol. 1994 Dec;197(1):437-42
references.pmid: 9318083
references.citation: Nature. 1983 Sep 22-28;305(5932):328-30
references.pmid: 6137771
references.citation: Peptides. 2007 Mar;28(3):585-93
references.pmid: 17141921
references.citation: Brain Res. 2003 Aug 29;982(2):156-67
references.pmid: 12915251
references.citation: Peptides. 2001 Feb;22(2):241-54
references.pmid: 11179818
references.citation: J Appl Physiol (1985). 2004 Feb;96(2):822-8
references.pmid: 14555689
references.citation: J Mol Cell Cardiol. 2006 Aug;41(2):330-9
references.pmid: 16806259
references.citation: Life Sci. 1982 Dec 6;31(23):2555-61
references.pmid: 7154851
references.citation: Trends Mol Med. 2007 Dec;13(12):503-11
references.pmid: 17981507
references.citation: Peptides. 2006 May;27(5):1073-86
references.pmid: 16500002
references.citation: Methods Cell Biol. 1997;52:307-22
references.pmid: 9379958
references.citation: Regul Pept. 1984 Apr;8(3):209-15
references.pmid: 6146997
references.citation: J Biol Chem. 2003 Sep 5;278(36):33694-700
references.pmid: 12815045
references.citation: J Mol Neurosci. 1992;3(4):213-8
references.pmid: 1390001
references.citation: Eur J Pharmacol. 2009 Oct 25;621(1-3):61-6
references.pmid: 19747477
references.citation: Biochim Biophys Acta. 2001 Sep 26;1540(3):221-32
references.pmid: 11583817
references.citation: J Biol Chem. 2001 Oct 5;276(40):36961-9
references.pmid: 11481330
references.citation: J Neurogenet. 1999 Jun;13(1-2):89-104
references.pmid: 10858818
references.citation: J Clin Invest. 1990 Oct;86(4):1164-71
references.pmid: 2120283
references.citation: Nat Cell Biol. 2000 Oct;2(10):703-8
references.pmid: 11025660
references.citation: J Comp Neurol. 2002 Jun 24;448(2):111-27
references.pmid: 12012424
references.citation: Science. 1977 Aug 12;197(4304):670-1
references.pmid: 877582
references.citation: J Biol Chem. 2005 Dec 16;280(50):41324-31
references.pmid: 16236710
references.citation: Biochem Biophys Res Commun. 1989 Apr 28;160(2):850-6
references.pmid: 2719702
references.citation: Annu Rev Entomol. 2003;48:485-503
references.pmid: 12414735
references.citation: Basic Res Cardiol. 1996;91 Suppl 2:35-40
references.pmid: 8957542
references.citation: J Exp Biol. 2009 Dec;212(Pt 24):3961-76
references.pmid: 19946074
references.citation: J Comp Physiol B. 2008 Sep;178(7):877-85
references.pmid: 18521612
references.citation: PLoS One. 2009 Dec 22;4(12):e8400
references.pmid: 20027225
references.citation: Neurosci Lett. 2001 Mar 16;300(3):153-6
references.pmid: 11226634