title: Subtype-specific control of P2X receptor channel signaling by ATP and Mg2+.
abstract: The identity and forms of activating ligands for ion channels are fundamental to their physiological roles in rapid electrical signaling. P2X receptor channels are ATP-activated cation channels that serve important roles in sensory signaling and inflammation, yet the active forms of the nucleotide are unknown. In physiological solutions, ATP is ionized and primarily found in complex with Mg(2+). Here we investigated the active forms of ATP and found that the action of MgATP(2-) and ATP(4-) differs between subtypes of P2X receptors. The slowly desensitizing P2X2 receptor can be activated by free ATP, but MgATP(2-) promotes opening with very low efficacy. In contrast, both free ATP and MgATP(2-) robustly open the rapidly desensitizing P2X3 subtype. A further distinction between these two subtypes is the ability of Mg(2+) to regulate P2X3 through a distinct allosteric mechanism. Importantly, heteromeric P2X2/3 channels present in sensory neurons exhibit a hybrid phenotype, characterized by robust activation by MgATP(2-) and weak regulation by Mg(2+). These results reveal the existence of two classes of homomeric P2X receptors with differential sensitivity to MgATP(2-) and regulation by Mg(2+), and demonstrate that both restraining mechanisms can be disengaged in heteromeric channels to form fast and sensitive ATP signaling pathways in sensory neurons.
authors: Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. mufeng_li@nih.gov
authors: Mufeng
authors: M
authors: Li
authors: Shai D
authors: SD
authors: Silberberg
authors: Kenton J
authors: KJ
authors: Swartz
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008274:Magnesium / Q000378:metabolism / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011487:Protein Conformation; D055503:Protein Multimerization; D051381:Rats; D058469:Receptors, Purinergic P2X / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058474:Receptors, Purinergic P2X1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058476:Receptors, Purinergic P2X2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058477:Receptors, Purinergic P2X3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058848:Receptors, Purinergic P2X4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D058469:Receptors, Purinergic P2X; D058474:Receptors, Purinergic P2X1; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D058848:Receptors, Purinergic P2X4; D000255:Adenosine Triphosphate; D008274:Magnesium
keywords: magnesium ATP; magnesium regulation
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