title: Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling.
abstract: Peptidergic signaling regulates cardiac contractility; thus, identifying molecular switches, ligand-receptor contacts, and antagonists aids in exploring the underlying mechanisms to influence health. Myosuppressin (MS), a decapeptide, diminishes cardiac contractility and gut motility. Myosuppressin binds to G protein-coupled receptor (GPCR) proteins. Two Drosophila melanogaster myosuppressin receptors (DrmMS-Rs) exist; however, no mechanism underlying MS-R activation is reported. We predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. Additionally, we believed DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 interactions would reflect our structure-activity relationship (SAR) data. We hypothesized agonist- and antagonist-receptor contacts would differ from one another depending on activity. Lastly, we expected our study to apply to other species; we tested this hypothesis in Rhodnius prolixus, the Chagas disease vector. Searching DrmMS-Rs for molecular switches led to the discovery of a unique ionic lock and a novel 3-6 lock, as well as transmission and tyrosine toggle switches. The DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 contacts suggested tissue-specific signaling existed, which was in line with our SAR data. We identified R. prolixus (Rhp)MS-R and discovered it, too, contained the unique myosuppressin ionic lock and novel 3-6 lock found in DrmMS-Rs as well as transmission and tyrosine toggle switches. Further, these motifs were present in red flour beetle, common water flea, honey bee, domestic silkworm, and termite MS-Rs. RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM. Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions. The active core docking mimicked RhpMS, however, the antagonist did not. Together, these data were consistent with the unique ionic lock, novel 3-6 lock, transmission switch, and tyrosine toggle switch being involved in mechanisms underlying TM movement and MS-R activation, and the ability of MS agonists and antagonists to influence physiology.
authors: Undergraduate Biochemistry Program, Chemistry Department, University of Michigan, Ann Arbor, Michigan, United States of America, 48109; Biological Chemistry Department, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 48109.
authors: Megan
authors: M
authors: Leander
authors: Biological Chemistry Department, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 48109; Undergraduate Chemistry Program, Chemistry Department, University of Michigan, Ann Arbor, Michigan, United States of America, 48109.
authors: Chloe
authors: C
authors: Bass
authors: Undergraduate Biochemistry Program, Chemistry Department, University of Michigan, Ann Arbor, Michigan, United States of America, 48109; Biological Chemistry Department, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 48109.
authors: Kathryn
authors: K
authors: Marchetti
authors: Undergraduate Biochemistry Program, Chemistry Department, University of Michigan, Ann Arbor, Michigan, United States of America, 48109; Biological Chemistry Department, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 48109.
authors: Benjamin F
authors: BF
authors: Maynard
authors: Laboratorio de Genética y Genómica Funcional, Centro Regional de Estudios Genómicos, Facultad de ciencias Exactas, Universidad Nacional de La Plata, Bv. 120 1459, Buenos Aires, Argentina.
authors: Juan Pedro
authors: JP
authors: Wulff
authors: Laboratorio de Genética y Genómica Funcional, Centro Regional de Estudios Genómicos, Facultad de ciencias Exactas, Universidad Nacional de La Plata, Bv. 120 1459, Buenos Aires, Argentina.
authors: Sheila
authors: S
authors: Ons
authors: Undergraduate Biochemistry Program, Chemistry Department, University of Michigan, Ann Arbor, Michigan, United States of America, 48109; Biological Chemistry Department, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 48109.
authors: Ruthann
authors: R
authors: Nichols
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D029721:Drosophila Proteins / Q000737:chemistry* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D018000:Receptors, Peptide / Q000737:chemistry* / Q000378:metabolism; D012239:Rhodnius / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D008024:Ligands; C478106:MsR1 protein, Drosophila; C478107:MsR2 protein, Drosophila; D010455:Peptides; D018000:Receptors, Peptide