Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling

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...

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Autores principales: Leander, Megan, Bass, Chloe, Marchetti, Kathryn, Maynard, Benjamin F., Wulff, Juan Pedro, Ons, Sheila, Nichols, Ruthann
Formato: Articulo
Lenguaje:Inglés
Publicado: 2015
Materias:
Ciencias Exactas
cardiac contractility
Rhodnius prolixus
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/85813
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-85813
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Exactas
cardiac contractility
Rhodnius prolixus
spellingShingle Ciencias Exactas
cardiac contractility
Rhodnius prolixus
Leander, Megan
Bass, Chloe
Marchetti, Kathryn
Maynard, Benjamin F.
Wulff, Juan Pedro
Ons, Sheila
Nichols, Ruthann
Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling
topic_facet Ciencias Exactas
cardiac contractility
Rhodnius prolixus
description 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 <i>Drosophila melanogaster</i> 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 <i>Rhodnius prolixus</i>, 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 <i>R. prolixus</i> (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 <i>R. prolixus</i> cardiac contractility dose dependently with EC<SUB>50</SUB> 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.
format Articulo
Articulo
author Leander, Megan
Bass, Chloe
Marchetti, Kathryn
Maynard, Benjamin F.
Wulff, Juan Pedro
Ons, Sheila
Nichols, Ruthann
author_facet Leander, Megan
Bass, Chloe
Marchetti, Kathryn
Maynard, Benjamin F.
Wulff, Juan Pedro
Ons, Sheila
Nichols, Ruthann
author_sort Leander, Megan
title Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling
title_short Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling
title_full Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling
title_fullStr Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling
title_full_unstemmed Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling
title_sort cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling
publishDate 2015
url http://sedici.unlp.edu.ar/handle/10915/85813
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