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.
Rocheville
Magalie
M
Department of Biological Reagents and Assay Development, GlaxoSmithKline, New Sciences Frontiers Park, Harlow CM19 5AW, UK. magalie.2.rocheville@gsk.com
Jerman
Jeff C
JC
D000818:Animals; D001665:Binding Sites; D001681:Biological Assay; D015195:Drug Design; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
D008024:Ligands; D043562:Receptors, G-Protein-Coupled; C450520:seven-transmembrane G-protein-coupled receptor