title: Allosteric functional switch of neurokinin A-mediated signaling at the neurokinin NK2 receptor: structural exploration.
abstract: The neurokinin NK2 receptor is known to pre-exist in equilibrium between at least three states: resting-inactive, calcium-triggering, and cAMP-producing. Its endogeneous ligand, NKA, mainly induces the calcium response. Using a FRET-based assay, we have previously discovered an allosteric modulator of the NK2 receptor that has the unique ability to discriminate among the two signaling pathways: calcium-signaling is not affected while cAMP signaling is significantly decreased. A series of compounds have been prepared and studied in order to better understand the structural determinants of this allosteric functional switch of a GPCR. Most of them display the same allosteric profile, with smooth pharmacomodulation. One compound however exhibits significantly improved modulatory properties of NKA induced signaling when compared to the original modulator.
authors.affiliation: UMR UdS/CNRS 7200, Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie, Illkirch, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Valant
authors.forename: Emeline
authors.initials: E
authors.lastname: Maillet
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bourguignon
authors.forename: Bernard
authors.initials: B
authors.lastname: Bucher
authors.forename: Valérie
authors.initials: V
authors.lastname: Utard
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Galzi
authors.forename: Marcel
authors.initials: M
authors.lastname: Hibert
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D020013:Calcium Signaling; D000242:Cyclic AMP; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D015288:Neurokinin A / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled; D018041:Receptors, Neurokinin-2 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D006841:Hydrocarbons, Aromatic; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D018041:Receptors, Neurokinin-2; D015288:Neurokinin A; D000242:Cyclic AMP