Abstract
Ionotropic glutamate receptors (iGluRs) mediate excitatory neuronal signaling in the mammalian CNS. These receptors are critically involved in diverse physiological processes; including learning and memory formation, as well as neuronal damage associated with neurological diseases. Based on partial sequence and structural similarities, these complex cation-permeable iGluRs are thought to descend from simple bacterial proteins emerging from a fusion of a substrate binding protein (SBP) and an inverted potassium (K+)-channel. Here, we fuse the pore module of the viral K+-channel KcvATCV-1 to the isolated glutamate-binding domain of the mammalian iGluR subunit GluA1 which is structural homolog to SBPs. The resulting chimera (GluATCV*) is functional and displays the ligand recognition characteristics of GluA1 and the K+-selectivity of KcvATCV-1. These results are consistent with a conserved activation mechanism between a glutamate-binding domain and the pore-module of a K+-channel and support the expected phylogenetic link between the two protein families.
Highlights
Ionotropic glutamate receptors mediate excitatory neuronal signaling in the mammalian central nervous system (CNS)
Gating of cation-permeable receptors by the amino acid glutamate mediating excitatory neuronal signaling in the mammalian CNS is crucially involved in both, learning and memory formation and pathological mechanisms leading to excitotoxic neuronal damage in diverse neurological diseases[1]
Our data demonstrate that a naive coupling of the ligand-binding domain (LBD) of the mammalian GluA1 subunit from the ionotropic glutamate receptor family with the viral potassium channel KcvATCV-1 generates a K+-selective, glutamate-gated receptor channel
Summary
Ionotropic glutamate receptors (iGluRs) mediate excitatory neuronal signaling in the mammalian CNS. Conversion of a chemical to an electrical signal is a hallmark of neurons in the central nervous system (CNS) This process is mediated by different families of ligand-gated ion-channels, membrane-spanning proteins that open upon recognition of a specific neurotransmitter. It has been shown that small viral K+-channels are because of their structural simplicity, functional robustness and the absence of any coevolution with cellular proteins most suitable as building blocks in synthetic channels where they maintain their conductive properties in the presence of attached regulatory domains[16,17,18] With this approach, we can show that the fusion of the LBD of GluA1 to the minimal K+-channel pore of KcvATCV-1 generates a truly glutamate-gated K+-channel. It implies a conserved activation mechanism of the pore region of iGluRs and ancestral viral K+-channels, which is gated by mechanical coupling to the LBD
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