TY - CHAP

T1 - Probing Biased Signaling in Chemokine Receptors

AU - Amarandi, Roxana Maria

AU - Hjortø, Gertrud Malene

AU - Rosenkilde, Mette Marie

AU - Karlshøj, Stefanie

PY - 2016

Y1 - 2016

N2 - The chemokine system mediates leukocyte migration during homeostatic and inflammatory processes. Traditionally, it is described as redundant and promiscuous, with a single chemokine ligand binding to different receptors and a single receptor having several ligands. Signaling of chemokine receptors occurs via two major routes, G protein- and β-arrestin-dependent, which can be preferentially modulated depending on the ligands or receptors involved, as well as the cell types or tissues in which the signaling event occurs. The preferential activation of a certain signaling pathway to the detriment of others has been termed signaling bias and can accordingly be grouped into ligand bias, receptor bias, and tissue bias. Bias has so far been broadly overlooked in the process of drug development. The low number of currently approved drugs targeting the chemokine system, as well as the broad range of failed clinical trials, reflects the need for a better understanding of the chemokine system. Thus, understanding the character, direction, and consequence of biased signaling in the chemokine system may aid the development of new therapeutics. This review describes experiments to assess G protein-dependent and -independent signaling in order to quantify chemokine system bias.

AB - The chemokine system mediates leukocyte migration during homeostatic and inflammatory processes. Traditionally, it is described as redundant and promiscuous, with a single chemokine ligand binding to different receptors and a single receptor having several ligands. Signaling of chemokine receptors occurs via two major routes, G protein- and β-arrestin-dependent, which can be preferentially modulated depending on the ligands or receptors involved, as well as the cell types or tissues in which the signaling event occurs. The preferential activation of a certain signaling pathway to the detriment of others has been termed signaling bias and can accordingly be grouped into ligand bias, receptor bias, and tissue bias. Bias has so far been broadly overlooked in the process of drug development. The low number of currently approved drugs targeting the chemokine system, as well as the broad range of failed clinical trials, reflects the need for a better understanding of the chemokine system. Thus, understanding the character, direction, and consequence of biased signaling in the chemokine system may aid the development of new therapeutics. This review describes experiments to assess G protein-dependent and -independent signaling in order to quantify chemokine system bias.

KW - 7TMR

KW - Bias

KW - cAMP

KW - Chemokine system

KW - Chemotaxis

KW - ERK

KW - GPCR

KW - GTPγS

KW - Internalization

KW - IP

KW - β-Arrestin

U2 - 10.1016/bs.mie.2015.09.001

DO - 10.1016/bs.mie.2015.09.001

M3 - Book chapter

C2 - 26921946

AN - SCOPUS:84959084638

VL - 570

T3 - Methods in Enzymology

SP - 155

EP - 186

BT - Methods in Enzymology

PB - Academic Press

ER -