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          Institute: MPI für medizinische Forschung     Collection: Max-Planck-Forschungsgruppe Ionenkanalstruktur (Dean R. Madden)     Display Documents



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ID: 23091.0, MPI für medizinische Forschung / Max-Planck-Forschungsgruppe Ionenkanalstruktur (Dean R. Madden)
The structure and function of glutamate receptor ion channels
Translation of Title:The structure and function of glutamate receptor ion channels
Authors:Madden, Dean R.
Language:English
Date of Publication (YYYY-MM-DD):2002-02
Title of Journal:Nature Neuroscience
Journal Abbrev.:Nat. Neurosci.
Volume:3
Issue / Number:2
Start Page:91
End Page:101
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:As in the case of many ligand-gated ion channels, the biochemical and electrophysiological properties of the ionotropic glutamate receptors have been studied extensively. Nevertheless, we still do not understand the molecular mechanisms that harness the free energy of agonist binding, first to drive channel opening, and then to allow the channel to close (desensitize) even though agonist remains bound. Recent crystallographic analyses of the ligand-binding domains of these receptors have identified conformational changes associated with agonist binding, yielding a working hypothesis of channel function. This opens the way to determining how the domains and subunits are assembled into an oligomeric channel, how the domains are connected, how the channel is formed, and where it is located relative to the ligand-binding domains, all of which govern the processes of channel activation and desensitization. New insights into the structures of glutamate receptor ion channels (iGluRs), combined with functional and biochemical data, can help us to understand how agonist binding triggers their activation and subsequent desensitization. Studies of related channels also provide valuable insights into the molecular basis of ion selectivity and transport. iGluRs are important for fast excitatory neural signalling and for synaptic plasticity. They are constructed from subunits that include an amino-terminal domain (NTD), a ligand-binding domain (S1S2), three transmembrane domains, a P-loop domain and a carboxy-terminal domain. The ligand-binding domain, S1S2, can be expressed and studied in isolation. It consists of two lobes that form a cleft, which is open at rest. When it binds agonist, the cleft closes around the ligand through a conformational change involving the formation of hydrogen bonds between the agonist and S1S2. The mechanism of closure involves an open⇔closed equilibrium for the ligand-binding domain. The balance of equilibrium shifts from the open to the closed state when it interacts with agonist. The ligand-binding site seems to possess several subsites that participate in ligand binding. Not all of these subsites need to be occupied for agonist binding, providing the flexibility to bind various agents. Vibrational spectroscopy shows that electronegative ligand moieties interact with electronegative groups in the binding site. It is not clear how the receptor subunits combine to form an ion channel. It is proposed that tetrameric channels form as a dimer of dimers, with initial dimerization being mediated by the NTDs, and the second dimerization of dimers requiring compatibility between the S2 and transmembrane domains. Current models of channel activation and desensitization involve cleft closure in each subunit, pulling the transmembrane domains of the subunit away from the pore axis, and thus opening the channel. The channel then closes by slippage between subunits. Glutamate receptors are permeable to both K+ and Na+, and in some cases to divalent cations. It seems likely that the channel opens wide enough to allow ions to pass through with their hydration shells. This contrasts with the K+ channels, in which ions are dehydrated at the entrance to the channel. Many questions remain to be answered about the ligand binding, activation, ion permeation and desensitization of iGluRs. The packing and symmetry of the P-loop sequence are unclear, as are the assembly interactions of the subunits. As these details become better understood, they will help us to understand the kinetics and selectivity of glutamate-gated channels.
External Publication Status:published
Document Type:Article
Communicated by:Wulf Kaiser
Affiliations:MPI für medizinische Forschung/Nachwuchsgruppe Ion Channel Structure
Identifiers:URI:http://www.nature.com/cgi-taf/DynaPage.taf?file=/n... [Fulltext HTML]
URI:http://www.nature.com/cgi-taf/DynaPage.taf?file=/n... [Abstract]
URI:http://www.nature.com/cgi-taf/DynaPage.taf?file=/n... [Fulltext PDF]
DOI:10.1038/nrn725
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