Purinergic P2X receptors (P2X1-7) are ligand-gated ion channels which binding sites for allosteric modulators are still not well understood. Activation of these receptors is the major signaling pathway of extracellular adenosine 5'-triphosphate (ATP) in neuroendocrine cells.
Purinergic P2X receptors (P2X1-7) are ligand-gated ion channels which binding sites for allosteric modulators are still not well understood. Ivermectin is a positive allosteric modulator of P2X4 receptor and exhibits no functional modulation of P2X2, P2X3 and P2X7 receptor activation, indicating that of these P2X receptors, only the P2X4 subtype is sensitive to ivermectin. Ivermectin alone does not activate the P2X4 receptor, but pre-application of the drug displays two distinct profound effects on the response of the receptor to agonist – potentiation of the response and increase in receptor sensitivity to ATP. Some current theories regarding the binding of IVM postulate that the two distinct effects of IVM are due to IVM binding at two distinct sites. We are using electrophysiological and molecular biology methods to identify crucial amino acids of the P2X4 receptor that are essential for ivermectin binding, and for ivermectin-induced changes in the pore of the ion channel. To understand ivermectin binding might help to design new compounds with pharmacological activity to allosterically modulate P2X4 receptors as well as other ivermectin-sensitive ligand gated ion channels, such as GABAA, nicotinic a7 and glycine receptors.
Ligand binding to P2X7 receptors opens dilated channel pore to control calcium influx and cell apoptosis. Characterization of the shift in reversal potential after P2X7-receptor stimulation when extracellular sodium is substituted with large organic cation NMDG provides a tool how to examine time course of dilation of the channel pore. These experiments, supplemented with structural analysis, allow mechanistic insights into receptor sensitivity and are crucial to understanding how P2X7 channels regulate apoptosis.