How the ligand changed its spots

At school it was simple; agonists produce a response, antagonists block it. But in time, we learn that life isn't so easy, and that efficacy comes in many shades. So, we classify ligands as full agonists, partial agonists, inverse agonists or silent antagonists. And just when we've got that sorted out, along come the drugs that can change their modus operandi depending on the circumstances. Pauwels et al. describe such a ligand, acting at the α_2A-adrenoceptor, in their recent paper in Neuropharmacology.

The literature contains few examples of ligands that seem to be able to both promote and decrease activity at the same G-protein-coupled receptors. Such 'protean ligands' — so-called after the mythical character Proteus, who could adopt any shape he desired — have been proposed to work by acting as agonists with low efficacy. They thereby increase the activity of receptors that are basically silent under resting conditions, but decrease the activity of receptors that have high levels of ligand-independent, spontaneous (or constitutive) activity. In this model, protean behaviour therefore depends on having two populations of receptors with different levels of spontaneous activity.

Pauwels et al. found that the activity of a dexefaroxan analogue — RX 831003 — at α_2A-adrenoceptors expressed in cultured cells depended on the nature of the co-expressed Gα-protein subunits. When adrenoceptor signalling was mediated by a Gα_oCys³⁵¹Ile protein, giving rise to considerable spontaneous activity, RX 831003 behaved as a partial inverse agonist. But when α_2A-adrenoceptors were co-expressed with Gα₁₅, resulting in a receptor complex without spontaneous activity, RX 831003 exhibited partial agonism.

As Gα₁₅ is not known to couple to α_2A-adrenoceptors in normal tissue, this precise in vitro difference is unlikely to be replicated in vivo. But the general demonstration that different G proteins might be able to induce ligands to reverse their actions at a single G-protein-coupled receptor suggests interesting possibilities for targeted activation, or deactivation, of subsets of receptor populations. Finding out how prevalent such behaviour really is will depend on pinning down the nature of the actual complexes that are formed by receptors and G proteins in vivo. A task not unlike getting the truth out of Proteus, who would adopt his true form and prophesy only when held fast by an interrogator.