Interleukins, from 1 to 37, and interferon\: Receptors, functions, and roles in diseases. neuropeptide receptorPK/PBANpyrokinin/pheromone biosynthesis\activating neuropeptideSHRspontaneously hypertensive ratsSpl\PK/PBAN\R larval pyrokinin/pheromone biosynthesis\activating neuropeptide receptoruPARurokinase\type plasminogen activator receptorWKYWistar KyotoymolyoctomoleyMyoctomolar (10?24M)zmolzeptomolezMzeptomolar (10?21M). 1.?INTRODUCTION There is evidence spanning a number of decades that describes cellular responses to sub\picomolar concentrations of various proteins, peptides, and other biologically active compounds (Table?1). While responses to these ultra\low concentrations are well documented and accepted by, for example, the cytokine field, within the GPCR field, such high receptor sensitivity is not typically recognised, and these responses are commonly overlooked. This view may be compounded by the fact that the majority of in vitro experiments in a wide variety of cell lines often rely on GPCR overexpression in order to BI-8626 increase the signal in the particular assay of interest, mainly due to a lack of assay sensitivity. As a result of this, GPCRs are typically accepted to respond to concentrations of active compounds within the nanomolar to BI-8626 millimolar range. Nevertheless, there are more than 35 published reports of GPCRs responding to ultra\low concentrations of ligand (Table?1). Interestingly, in the majority of cases, these observations come from endogenous, and not overexpression, systems. Here, we aim to describe the evidence for this ultra\sensitive signalling to reveal that this is not limited to a few family A receptors (Civciristov et al., 2018; Halls & Cooper, 2010). Rather, many prototypical and well\studied GPCRs can respond to BI-8626 attomolar/femtomolar concentrations of ligand. The ability of so many GPCRs to respond to such ultra\low concentrations of ligand suggests that a better understanding of this sensitivity will be of great importance for future research and drug discovery. While the main focus of this review will be GPCRs, they are not the only receptors that mediate remarkably ultra\sensitive responses. Hence, we also briefly describe examples of ultra\sensitive biological responses mediated by IL receptors, ion channels, nuclear receptors, and ganglioside receptors. Table 1 Summary of literature demonstrating GPCR responses to sub\picomolar concentrations of ligand diapause hormone; MT: myotropin; LPK: Leucophaea maderae pyrokinin; \SGNP: \subesophageal neuropeptide; PBAN: Helicoverpa zea PBAN. Concentration unitspM: picomolar (10?12?M); fM: femtomolar (10?15?M); aM: attomolar (10?18?M); zM: zeptomolar (10?21?M); ACTH: adrenocorticotropic hormone; Rabbit polyclonal to Bcl6 DAA\I: des\Asp\angiotensin I; DAMEA: [D\ala2]methionine enkephalinamide; DOR, receptors; MOR, receptors; IP: inositol phosphate. 2.?IL RECEPTORS Since the initial identification and characterisation of IL\1 (Auron et al., 1984; Lomedico et al., 1984), more than 40 ILs have been identified (Akdis et al., 2011). The IL family of cytokines are highly potent molecules (potency in the femtomolar range) that are able to evoke a cellular response by activating only one or two receptors per cell (reviewed in Dinarello, 1994). The ILs exert their biological function by principally binding two major receptor families: the type I and II cytokine receptors. IL\1 binds to and activates a type I cytokine receptor, and several early studies clearly demonstrate the high potency of recombinant IL\1. Treatment of quiescent BALB/c\3T3 fibroblasts with 60 fM recombinant IL\1 resulted in increased expression of the chemokines CCL2 and CXCL1, both of which have important roles in inflammation and immunomodulation (Hall, Brownlee, & Stiles, 1989). Moreover, treatment of human synovial fibroblasts with 0.6C600 fM of recombinant human IL\1 increased the production of PGE and collagenase (Meyer, Yaron, & Yaron, 1990). Ultra\low concentrations of IL\1 also have more global effects in physiological systems. Treatment of rat brain slices with 0.1 aMC1 fM recombinant rat IL\1 triggered a concentration\dependent decrease in glutamatergic transmission, as measured by the field EPSP (Luk et al., 1999). While IL\1 exerts its effects via a type I cytokine receptor, IFNs activate type II cytokine receptors and can do so at ultra\low concentrations. In human mature macrophages differentiated from monocytes, 3 fM IFN\2 and IFN\ caused BI-8626 suppression of IFN\ mediated H2O2 release (Yoshida, Murray, & Nathan, 1988). The authors speculated that this could be an important protective mechanism. During inflammation, high concentrations of cytokines can potentially diffuse from inflamed tissues towards normal tissues and cause destructive, off\target effects. Therefore, ultra\low concentrations of IFN\2 and IFN\ could be important for suppression of the aberrant release of H2O2 in healthy tissue. These studies demonstrate the first robust evidence of cellular responses to ultra\low concentrations of ligand and highlight the importance of this sensitivity in the initiation and.