7TM pharmacology measured by label-free: a holistic approach to cell signalling

Ligands acting at 7-transmembrane receptors (7TMs) transduce effects on cellular behaviour in a notion termed efficacy; in turn, the cellular behaviour or phenotype can be quantified. Underpinning efficacy is the ability of ligands to dictate the triggering of distinct intracellular signalling event(s) in a system-dependent manner through selective stabilisation of receptor conformations. Given the wealth of putative cell signalling routes a receptor species may possess (spectrum of activities) and numerous mechanisms by which ligand–receptor pairings signal, the call for an integrated solution to cellular activity has come to light. The potential of novel methodologies to probe for 7TM function such as label-free has been subjected to much attention in recent years. Label-free detection differs greatly from the arsenal of the so-called traditional 7TM techniques commonly employed. It provides a temporally resolved cumulative readout of cellular activity using intact and living cells. It holds vast promise in enabling cellular behaviours to be estimated in a global or ‘holistic’ manner. This article will focus on key 7TM areas of interest where label-free has been particularly impactful of late rather than covering the principles behind the methodologies (which have been reviewed elsewhere). Firstly, it has facilitated the detection of endogenous or native-like cellular systems that are possibly more physiologically relevant; secondly, it has offered unprecedented angles to the probing of functional selectivity and ligand efficacy.