Journal article
Cardiac Contractility Structure-Activity Relationship and Ligand-Receptor Interactions; the Discovery Of Unique and Novel Molecular Switches in Myosuppressin Signaling
PloS one, Vol.10(3), pp.e0120492-e0120492
03/20/2015
DOI: 10.1371/journal.pone.0120492
PMCID: PMC4368603
PMID: 25793503
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.
Details
- Title: Subtitle
- Cardiac Contractility Structure-Activity Relationship and Ligand-Receptor Interactions; the Discovery Of Unique and Novel Molecular Switches in Myosuppressin Signaling
- Creators
- Megan Leander - University of MichiganChloe Bass - University of MichiganKathryn Marchetti - University of MichiganBenjamin F. Maynard - University of MichiganJuan Pedro Wulff - Universidad Nacional de La PlataSheila Ons - Universidad Nacional de La PlataRuthann Nichols - University of Michigan
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.10(3), pp.e0120492-e0120492
- DOI
- 10.1371/journal.pone.0120492
- PMID
- 25793503
- PMCID
- PMC4368603
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library Science
- Number of pages
- 40
- Grant note
- Albert Euclid Hinsdale Award University of Michigan Medical Innovation Center University of Michigan Cardiovascular Center Innovative Grant R21HL093627 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Seyhan N. Ege-WISE Award Honors Summer Fellowship
- Language
- English
- Date published
- 03/20/2015
- Academic Unit
- Urology
- Record Identifier
- 9984848427602771
Metrics
1 Record Views