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dc.contributor.author
Leander, Megan
dc.contributor.author
Bass, Chloe
dc.contributor.author
Marchetti, Kathryn
dc.contributor.author
Maynard, Benjamin F.
dc.contributor.author
Wulff, Juan Pedro
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dc.contributor.author
Ons, Sheila
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dc.contributor.author
Nichols, Ruthann
dc.date.available
2018-07-30T17:21:37Z
dc.date.issued
2015-03
dc.identifier.citation
Leander, Megan; Bass, Chloe; Marchetti, Kathryn; Maynard, Benjamin F.; Wulff, Juan Pedro; et al.; Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling; Public Library of Science; Plos One; 10; 3; 3-2015; 1-40; e0120492
dc.identifier.issn
1932-6203
dc.identifier.uri
http://hdl.handle.net/11336/53412
dc.description.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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Public Library of Science
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Myosuppressin
dc.subject
Cardiac Contractily
dc.subject
Agonist
dc.subject
Antagonis
dc.subject.classification
Otras Ciencias Biológicas
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-07-30T13:38:10Z
dc.journal.volume
10
dc.journal.number
3
dc.journal.pagination
1-40; e0120492
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
San Francisco
dc.description.fil
Fil: Leander, Megan. University of Michigan; Estados Unidos
dc.description.fil
Fil: Bass, Chloe. University of Michigan; Estados Unidos
dc.description.fil
Fil: Marchetti, Kathryn. University of Michigan; Estados Unidos
dc.description.fil
Fil: Maynard, Benjamin F.. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Wulff, Juan Pedro. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Ons, Sheila. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina
dc.description.fil
Fil: Nichols, Ruthann. University of Michigan; Estados Unidos
dc.journal.title
Plos One
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1371/journal.pone.0120492
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368603/
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120492
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