Wang Tzu-Ming, Brown Brandon M, Deng Lunbin, Sellers Benjamin D, Lupardus Patrick J, Wallweber Heidi J A, Gustafson Amy, Wong Evera, Volgraf Matthew, Schwarz Jacob B, Hackos David H, Hanson Jesse E
Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Neuropharmacology. 2017 Jul 15;121:204-218. doi: 10.1016/j.neuropharm.2017.04.041. Epub 2017 Apr 27.
Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools have yielded insight into iGluR extracellular domain function, less is known about molecular mechanisms underlying the ion conduction gating process within the transmembrane domain (TMD). We have discovered a novel NMDAR positive allosteric modulator (PAM), GNE-9278, with a unique binding site on the extracellular surface of the TMD. Mutation of a single residue near the Lurcher motif on GluN1 M3 can convert GNE-9278 modulation from positive to negative, and replacing three AMPAR pre-M1 residues with corresponding NMDAR residues can confer GNE-9278 sensitivity to AMPARs. Modulation by GNE-9278 is state-dependent and significantly alters extracellular domain pharmacology. The unique properties and structural determinants of GNE-9278 reveal new modulatory potential of the iGluR TMD.
离子型谷氨酸受体（iGluRs）介导快速兴奋性神经传递，是关键的神经系统药物靶点。虽然多种药理学工具已让人们深入了解iGluR细胞外结构域的功能，但对于跨膜结构域（TMD）内离子传导门控过程的分子机制却知之甚少。我们发现了一种新型NMDAR正变构调节剂（PAM）GNE-9278，它在TMD的细胞外表面有一个独特的结合位点。GluN1 M3上靠近Lurcher模体的单个残基发生突变，可使GNE-9278的调节作用从正向变为负向，用相应的NMDAR残基替换三个AMPAR M1前体残基可使AMPAR对GNE-9278敏感。GNE-9278的调节作用具有状态依赖性，并显著改变细胞外结构域药理学。GNE-9278的独特性质和结构决定因素揭示了iGluR TMD新的调节潜力。
