Allosteric modulation of Ca2+ flux in ligand-gated cation channel (P2X4) by actions on lateral portals.
Human P2X receptors are a family of seven ATP-gated ion channels that transport Na(+), K(+), and Ca(2+) across cell surface membranes. The P2X4 receptor is unique among family members in its sensitivity to the macrocyclic lactone, ivermectin, which allosterically modulates both ion conduction and channel gating. In this paper we show that removing the fixed negative charge of a single acidic amino acid (Glu(51)) in the lateral entrance to the transmembrane pore markedly attenuates the effect of ivermectin on Ca(2+) current and channel gating. Ca(2+) entry through P2X4 receptors is known to trigger downstream signaling pathways in microglia. Our experiments show that the lateral portals could present a novel target for drugs in the treatment of microglia-associated disease including neuropathic pain.
Department of Pharmacological and Physiological Science and The Center for Excellence in Neuroscience, Saint Louis University School of Medicine, St. Louis, Missouri, 63130, USA.
Damien S K
DS
Samways
Baljit S
BS
Khakh
Terrance M
TM
Egan
D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D019943:Amino Acid Substitution; D000977:Antiparasitic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002461:Cell Line, Transformed; D006801:Humans; D015640:Ion Channel Gating; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D007559:Ivermectin / Q000494:pharmacology; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D058848:Receptors, Purinergic P2X4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D000977:Antiparasitic Agents; D009419:Nerve Tissue Proteins; D058848:Receptors, Purinergic P2X4; D007559:Ivermectin; D002118:Calcium