Seeking ligand bias: assessing GPCR coupling to β-arrestins for drug discovery

G-protein-coupled receptors (GPCR) are the major sites of action for endogenous hormones and neurotransmitters. Early drug discovery efforts focused on determining whether ligands could engage G protein coupling and subsequently activate or inhibit cognate ‘second messengers.’ Gone are those simple days as we now realize that receptors can also couple β-arrestins. As we delve into the complexity of ligand-directed signaling and receptosome scaffolds, we are faced with what may seem like endless possibilities triggered by receptor–ligand-mediated events.

Introduction

GPCRs are ideal targets for pharmaceutical development with the goal of either mimicking the normal transmitter response or tempering it. In recent years, targeting GPCRs has become more complicated as we realize that drug action at receptors is ‘context dependent’ such that activation and inhibition are limited to the response evaluated and ‘agonist’ and ‘antagonist’ become terms that reflect a particular condition of the experimental or physiological output [1, 2, 3]. Further, we have realized that GPCRs couple to other proteins besides G proteins. Of these, the β-arrestins have proven to be crucial regulators of GPCR signaling. Therefore, rather than limiting the concept of receptor activation to its coupling to a particular G protein, GPCR signaling may be envisioned as an event caused by a ligand-mediated conformational shift in receptor structure that leads to rearrangement of a signaling scaffold to recruit or dispel certain signaling players. In this sense β-arrestins play a pivotal role in determining what players are recruited or rejected, and thus, acting as facilitators, stabilizers or dampening agents, function in directing GPCR signaling.

In recent years, signaling via β-arrestins has been demonstrated in cell culture models for many GPCRs (see [4 for review]) and there appears to be some bias whereby certain ligands will preferentially engage β-arrestins to activate particular cascades [5, 6, 7]. An interesting example of this is carvedilol, which has been known as a ‘beta-blocker’ but now has been shown to activate ERK pathways via β-arrestin-dependent signaling mechanisms suggesting that it is an ‘activator’ at the β2 adrenergic receptor with respect to this pathway [6]. As the implications of the β-arrestin-directed signaling pathways begin to emerge in cellular and in animal studies [8], screening for both β-arrestin interaction and second messenger activation may prove to be an important early step in drug discovery efforts.