Kinetic profiling an abundantly expressed planarian serotonergic GPCR identifies bromocriptine as a perdurant antagonist. Int J Parasitol Drugs Drug Resist 2016 Dec;6(3):356-363
Date
07/12/2016Pubmed ID
27397764Pubmed Central ID
PMC5196488DOI
10.1016/j.ijpddr.2016.06.002Scopus ID
2-s2.0-85003481158 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
The diversity and uniqueness of flatworm G protein coupled receptors (GPCRs) provides impetus for identifying ligands useful as tools for studying flatworm biology, or as therapeutics for treating diseases caused by parasitic flatworm infections. To catalyse this discovery process, technologies optimized for mammalian GPCR high throughput screening need be transposed for screening flatworm GPCRs. Here, we demonstrate the utility of a genetically encoded cAMP biosensor for resolving the properties of an abundantly expressed planarian serotonergic GPCR (S7.1R). Application of this methodology resolved the real time kinetics of GPCR modulation by ligands and demonstrated a marked difference in the kinetic action of antagonists at S7.1R. Notably, bromocriptine caused a protracted inhibition of S7.1R activity in vitro and a protracted paralysis of planarian movement, replicating the effect of S7.1R in vivo RNAi. The lengthy inhibition of function caused by bromocriptine at this abundantly expressed GPCR provides a useful tool to ablate serotonergic signaling in vivo, and is a noteworthy feature for exploitation as an anthelmintic vulnerability.
Author List
Chan JD, Grab T, Marchant JSAuthor
Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnthelmintics
Bromocriptine
Drug Evaluation, Preclinical
Kinetics
Locomotion
Planarians
Receptors, G-Protein-Coupled
Serotonergic Neurons
Serotonin Antagonists