An S-Palmitoyltransferase Modulates P2X7 Function
The P2X7 receptor is an ATP gated ion channel that plays significant roles in the immune response and neurodegeneration. In a heterologous system, P2X7 channels open only when triggered by a high concentration of ATP (EC50 [ALMOST EQUAL TO] 100 to 1000 [MICRO SIGN]M), suggesting that P2X7 receptors may function under pathological conditions. However, it remains unclear whether P2X7 functions under physiological conditions, in which extracellular concentrations of ATP are generally much lower. Here, I show that interaction with DHHC11, a palmitoyltransferase, modifies P2X7 gating in a manner independent from its palmitoyltransferase activity. This interaction sensitizes the P2X7 receptor to lower concentrations of ATP and slows its activation and deactivation, but does not affect the so-called "dilated state" where the P2X7 channel becomes permeable to large cations. Modified P2X7 currents were still seen with deletion of the P2X7 N- and C- termini, as well as with the deletions of the DHHC11 termini. I developed a computational Markov state model and successfully replicated the observed modifications of the P2X7 receptor by DHHC11. This represents a potential interaction between P2X7 and DHHC11, which implies yet undiscovered roles of P2X7 receptor under physiological conditions.
Dando, Robin; Oswald, Robert Edward
Master of Science
dissertation or thesis