Bias in chemokine receptor signalling

Zweemer, Annelien J.M.; Toraskar, Jimita Prashant; Heitman, Laura H.; IJzerman, Adriaan P.

doi:10.1016/j.it.2014.02.004

Cited by 76 publications

(69 citation statements)

References 88 publications

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“…The concept of signaling bias in GPCRs with multiple endogenous ligands is not unusual and, indeed, has been widely reported within the chemokine receptor family. 143,144 Although currently no studies have directly assessed LCFA-mediated signaling bias at FFA1, one recent review has suggested that abnormal activation of FFA1 by conjugated linoleic acids may account for the particularly strong lipotoxic effects of this series of LCFA. 145 Clearly further work is needed in this area to fully elucidate involvement of FFA1 in the effects of different LCFAs on β-cells and insulin secretion.…”

Section: Lcfas At Ffa1mentioning

confidence: 99%

Complex Pharmacology of Free Fatty Acid Receptors

et al. 2016

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G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond simple competitive agonism or antagonism by ligands interacting with the orthosteric binding site of the receptor to incorporate concepts of allosteric agonism, allosteric modulation, signaling bias, constitutive activity, and inverse agonism. Herein, we consider how evolving concepts of GPCR pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential.

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Section: Lcfas At Ffa1mentioning

confidence: 99%

Complex Pharmacology of Free Fatty Acid Receptors

et al. 2016

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“…Signal bias is certainly not restricted to synthetic ligands. For example, endogenous ligands for chemokine receptors clearly exert bias (Zweemer et al, 2014), and receptors, such as FFA2, that respond to multiple endogenously generated ligands may have the potential to display variation in signal flux.…”

Section: Experimental Challenges and Current Perspectives For The Valmentioning

confidence: 99%

The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

et al. 2015

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Despite some blockbuster G protein-coupled receptor (GPCR) drugs, only a small fraction (∼15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2-6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation byproducts of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic b-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair.

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“…Biased signaling appears to be ubiquitous among CKRs, and it provides a framework for understanding how a finite cast of ligands generates myriad functionally diverse outcomes. Biased signaling has been subdivided into three categories: ligand bias, receptor bias and cellular or tissue bias [4, 5, 181, 182]. …”

Section: Beyond Canonical Chemokine Receptor Signalingmentioning

confidence: 99%

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model

Kleist

Getschman

Ziarek

et al. 2016

Biochemical Pharmacology

106

113

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Chemokine receptor (CKR) signaling forms the basis of essential immune cellular functions, and dysregulated CKR signaling underpins numerous disease processes of the immune system and beyond. CKRs, which belong to the seven transmembrane domain receptor (7TMR) superfamily, initiate signaling upon binding of endogenous, secreted chemokine ligands. Chemokine-CKR interactions are traditionally described by a two-step/two-site mechanism, in which the CKR N-terminus recognizes the chemokine globular core (i.e. site 1 interaction), followed by activation when the unstructured chemokine N-terminus is inserted into the receptor TM bundle (i.e. site 2 interaction). Several recent studies challenge the structural independence of sites 1 and 2 by demonstrating physical and allosteric links between these supposedly separate sites. Others contest the functional independence of these sites, identifying nuanced roles for site 1 and other interactions in CKR activation. These developments emerge within a rapidly changing landscape in which CKR signaling is influenced by receptor PTMs, chemokine and CKR dimerization, and endogenous non-chemokine ligands. Simultaneous advances in the structural and functional characterization of 7TMR biased signaling have altered how we understand promiscuous chemokine-CKR interactions. In this review, we explore new paradigms in CKR signal transduction by considering studies that depict a more intricate architecture governing the consequences of chemokine-CKR interactions.

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Bias in chemokine receptor signalling

Cited by 76 publications

References 88 publications

Complex Pharmacology of Free Fatty Acid Receptors

Complex Pharmacology of Free Fatty Acid Receptors

The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model

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