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.

Gender-Related Differences of Tachykinin NK2Receptor Expression and Activity in Human Colonic Smooth Muscle

“…Interestingly, the antagonistic activity of ibodutant at the NK2 receptor appears agonist-dependent in males with a higher potency against LMN-NKA compared to NKA. NK2 receptors can couple to both Gαq/11 and Gαs proteins, and different ligands can stabilise distinct NK2 receptor states, leading to the activation of different downstream pathways (Palanche et al, 2001;Maillet et al, 2007;Valant et al, 2009).…”

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

“…This shift in conformation populations results in a slight potentiation of agonist-induced calcium response, indicating a possible increase of this particular conformation. Further modification on 184 to 185 with a butyronitrile side chain yielded a compound that retains suppression of cAMP production while increasing potentiation of agonist-induced calcium mobilization E max (50% to 68%) . Additional efforts toward NK2 NAMs may elucidate the discrepancies between active conformations and provide evidence for NAMs as therapeutic candidates for gastrointestinal-related diseases.…”

Les récepteurs couplés aux protéines G

“…Une telle possibilité, confortée par la proximité de ces domaines ( Figure 4A) [35], fait actuellement l'objet de recherches intenses visant à l'obtention de molécules très affines et très sélectives [25,26]. En ce qui concerne le récepteur NK2 des tachykinines, un autre RCPG de classe A, il a été montré que le modulateur allostérique LPI 805 affectait différemment les réponses engendrées par la neurokinine A [15,27]. En effet, il déstabilise l'état actif tardif couplé à la proautres les arrestines, les protéines RAMP (receptor activity modifying proteins) et les pepducines, une nouvelle famille de peptides qui activent des RCPG par leur côté intracellulaire [22].…”

“…AC : adénylate cyclase ; PLC : phospholipase C. B. Modulation allostérique de l'activation du récepteur NK2 des tachykinines. Le composé LPI 805 se lie au niveau d'un site distinct du récepteur et se comporte comme un inhibiteur partiel et non compétitif de la liaison de NKA [15,27]. Il stabilise la formation des complexes C 1 L au détriment de l'état C 2 .…”