Agonist potency at P2X7 receptors is modulated by structurally diverse lipids

Br J Pharmacol. 2007 Oct;152(4):523-37. doi: 10.1038/sj.bjp.0707417. Epub 2007 Aug 13.


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.

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Animals
  • Calcium / metabolism
  • Cell Line
  • Dose-Response Relationship, Drug
  • Ethidium / metabolism
  • Fluorometry
  • Humans
  • Interleukin-1beta / metabolism
  • Lipids / chemistry
  • Lipids / pharmacology*
  • Lysophosphatidylcholines / chemistry
  • Lysophosphatidylcholines / pharmacology
  • Mice
  • Octoxynol / pharmacology
  • Palmitoylcarnitine / chemistry
  • Palmitoylcarnitine / pharmacology
  • Phosphorylcholine / analogs & derivatives
  • Phosphorylcholine / chemistry
  • Phosphorylcholine / pharmacology
  • Purinergic P2 Receptor Agonists*
  • Radioligand Assay
  • Rats
  • Receptors, Purinergic P2 / genetics
  • Receptors, Purinergic P2 / metabolism*
  • Receptors, Purinergic P2X2
  • Receptors, Purinergic P2X7
  • Sphingosine / analogs & derivatives
  • Sphingosine / chemistry
  • Sphingosine / pharmacology
  • Surface-Active Agents / chemistry
  • Surface-Active Agents / pharmacology


  • Interleukin-1beta
  • Lipids
  • Lysophosphatidylcholines
  • P2RX2 protein, human
  • P2RX7 protein, human
  • P2rx2 protein, mouse
  • P2rx7 protein, mouse
  • Purinergic P2 Receptor Agonists
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2X2
  • Receptors, Purinergic P2X7
  • Surface-Active Agents
  • sphingosine phosphorylcholine
  • Phosphorylcholine
  • Palmitoylcarnitine
  • Adenosine Triphosphate
  • Octoxynol
  • Ethidium
  • Sphingosine
  • Calcium