Signalling in response to sub‐picomolar concentrations of active compounds: Pushing the boundaries of GPCR sensitivity

Abstract

There is evidence for ultra‐sensitive responses to active compounds at concentrations below picomolar levels by proteins and receptors found in species ranging from bacteria to mammals. We have recently shown that such ultra‐sensitivity is also demonstrated by a wide range of prototypical GPCRs, and we have determined the molecular mechanisms behind these responses for three family A GPCRs: the relaxin receptor, RXFP1; the β2‐adrenoceptor; and the M3 muscarinic ACh receptor. Interestingly, there are reports of similar ultra‐sensitivity by more than 15 human GPCR families, in addition to other human receptors and channels. These occur through a diverse range of signalling pathways and produce modulation of important physiological processes, including neuronal transmission, chemotaxis, gene transcription, protein/ion uptake and secretion, muscle contraction and relaxation, and phagocytosis. Here, we summarise the accumulating evidence of ultra‐sensitive receptor signalling to show that this is a common, though currently underappreciated, property of GPCRs. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

Dual modulation of formyl peptide receptor 2 by aspirin‐triggered lipoxin contributes to its anti‐inflammatory activity

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Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants

“…G proteins, including Gq, can exist as preassembled protein complexes with GPCRs, in which the receptor, G proteins and effectors exist in very close proximity to each other in the absence of ligand (Qin et al, 2011). This close proximity leads to the presence of "high affinity" receptors (Civciristov et al, 2018), in which the presence of a ligand leads to a rapid increase in signaling due to mechanisms that may include rebinding of ligand, increased ligand binding time and increased ligand sequestration/concentration (Dityatev and Schachner, 2006;Herbette et al, 1988; Disease Models & Mechanisms • DMM • Accepted manuscript Hrabetová and Nicholson, 2004;Kane et al, 2008;Sargent et al, 1988;Sykes et al, 2014;Vargová and Syková, 2008;Vauquelin and Charlton, 2010). These high affinity receptors can also respond to ultralow ligand concentrations (Civciristov et al, 2018).…”

“…This close proximity leads to the presence of "high affinity" receptors (Civciristov et al, 2018), in which the presence of a ligand leads to a rapid increase in signaling due to mechanisms that may include rebinding of ligand, increased ligand binding time and increased ligand sequestration/concentration (Dityatev and Schachner, 2006;Herbette et al, 1988; Disease Models & Mechanisms • DMM • Accepted manuscript Hrabetová and Nicholson, 2004;Kane et al, 2008;Sargent et al, 1988;Sykes et al, 2014;Vargová and Syková, 2008;Vauquelin and Charlton, 2010). These high affinity receptors can also respond to ultralow ligand concentrations (Civciristov et al, 2018). The remaining receptors that are not part of a preassembled complex are considered low affinity receptors and respond to high ligand concentrations (Civciristov et al, 2018).…”

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