Related Experiment Video
Updated: Jul 13, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Agonist potency at P2X7 receptors is modulated by structurally diverse lipids
1Neurology & GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Limited, New Frontiers Science Park, Harlow, Essex, UK. adm7393@gsk.com
Background And Purpose:
The P2X(7) receptor exhibits a high degree of plasticity with agonist potency increasing after prolonged receptor activation. In this study we investigated the ability of lipids to modulate agonist potency at P2X(7) receptors.
Experimental Approach:
A variety of lipids, including lysophosphatidylcholine, sphingosylphosphorylcholine and hexadecylphosphorylcholine were studied for their effect on P2X(7) receptor-stimulated ethidium bromide accumulation in cells expressing human recombinant P2X(7) receptors and on P2X(7) receptor-stimulated interleukin-1 beta (IL1 beta) release from THP-1 cells. The effects of the lipids were also assessed in radioligand binding studies on human P2X(7) receptors.
Key Results:
At concentrations (3-30 microM) below the threshold to cause cell lysis, the lipids increased agonist potency and/or maximal effects at P2X(7) receptors in both ethidium accumulation and IL1 beta release studies. There was little structure activity relationship (SAR) for this effect and sub-lytic concentrations of Triton X-100 partially mimicked the effects of the lipids. The lipids caused cell lysis and increased intracellular calcium at higher concentrations (30-100 microM) which complicated interpretation of their effects in functional studies. However, the lipids (3-100 microM) also increased agonist potency 30-100 fold in radioligand binding studies.
Conclusions And Implications:
This study demonstrates that a diverse range of lipids increase agonist potency at the P2X(7) receptor in functional and binding studies. The broad SAR, including the effect of Triton X-100, suggests this may reflect changes in membrane properties rather than a direct effect on the P2X(7) receptor. Since many of the lipids studied accumulate in disease states they may enhance P2X(7) receptor function under pathophysiological conditions.
Related Concept Videos
Drug-Receptor Interaction: Agonist
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous ligand's action.
Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
Ligand-Gated Ion Channel Receptor: Gating Mechanism
GPCRs Regulate Adenylyl Cylase Activity
Two...
Drug-Receptor Interactions
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue.
Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
The direct-acting...
