Elementary Steps in Synaptic Transmission Revealed by Currents Through Single Ion Channels

Sakmann, Bert

doi:10.1007/978-3-642-84949-7_1

Cited by 7 publications

(10 citation statements)

References 54 publications

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“…This would serve to reduce the diameter of the pentamer near the extracellular membrane face by B1 Å . Minimal conformational change in the vicinity of the linking region might be expected in the AChR, since the transitions between the open channel and resting states are rapid and require small differences in energy states (Sakmann, 1992). Nevertheless, it is unclear whether such conformational differences are part of the linkage in the gating mechanism, since AChBP lacks the complement of residues necessary in the functioning receptor to couple to channel gating (Bouzat et al, 2004).…”

Section: Conformational Fit For Nicotinic Antagonists and Agonistsmentioning

confidence: 99%

Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations

Hansen

Sulzenbacher

Huxford

et al. 2005

EMBO J

618

953

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Upon ligand binding at the subunit interfaces, the extracellular domain of the nicotinic acetylcholine receptor undergoes conformational changes, and agonist binding allosterically triggers opening of the ion channel. The soluble acetylcholine-binding protein (AChBP) from snail has been shown to be a structural and functional surrogate of the ligand-binding domain (LBD) of the receptor. Yet, individual AChBP species display disparate affinities for nicotinic ligands. The crystal structure of AChBP from Aplysia californica in the apo form reveals a more open loop C and distinctive positions for other surface loops, compared with previous structures. Analysis of Aplysia AChBP complexes with nicotinic ligands shows that loop C, which does not significantly change conformation upon binding of the antagonist, methyllycaconitine, further opens to accommodate the peptidic antagonist, a-conotoxin ImI, but wraps around the agonists lobeline and epibatidine. The structures also reveal extended and nonoverlapping interaction surfaces for the two antagonists, outside the binding loci for agonists. This comprehensive set of structures reflects a dynamic template for delineating further conformational changes of the LBD of the nicotinic receptor.

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Section: Conformational Fit For Nicotinic Antagonists and Agonistsmentioning

confidence: 99%

Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations

Hansen

Sulzenbacher

Huxford

et al. 2005

EMBO J

618

953

View full text Add to dashboard Cite

show abstract

“…Thus, it is expected that the conformational changes induced upon agonist and antagonist binding should lead to different amino acid interactions that lead to either the channel opening or remaining shut. Minimal conformational changes are expected to occur in the binding site upon ligand binding as channel opening is rapid and requires only small differences in energy states (66).…”

Section: Our Model Differentiates Between Amino Acids Involved In Binmentioning

confidence: 99%

A Molecular Basis for Agonist and Antagonist Actions at GABA_C Receptors

et al. 2008

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We modelled the N-terminal ligand-binding domain of the rho1 GABA(C) receptor based on the Lymnaea stagnalis acetylcholine-binding protein (L-AChBP) crystal structure using comparative modelling and validated using flexible docking guided by known mutagenesis studies. A range of known rho1 GABA(C) receptor ligands comprising seven full agonists, 10 partial agonists, 43 antagonists and 12 inactive molecules were used to evaluate and validate the models. Of the 50 models identified, six models that allowed flexible ligand docking in accordance with the experimental data were selected and used to study detailed receptor-ligand interactions. The most refined model to accommodate all known active ligands featured a cavity comprising of a volume of 488 A(3). A detailed analysis of the interaction between the rho1 GABA(C) receptor model and the docked ligands revealed possible H-bonds and cation-pi interactions between the different ligands and binding site residues. Based on quantum mechanical/molecular mechanical (QM/MM) calculations, the model showed distinctive conformations of loop C that provided a molecular basis for agonist and antagonist actions. Agonists elicit loop C closure, while a more open loop C was observed upon antagonist binding. The model differentiates the role for key residues known to be involved in either binding and/or gating.

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“…The potent combination of electrophysiology and molecular cloning has allowed a dramatic advance in our understanding of post-synaptic events. Three classes of post-synaptic ionotropic (possessing an integral ion channel) glutamate receptors have been identified and cloned: the 2-amino-3hydroxy-5-methyl-4-isoxazole propionatekainate (AMPA/ KA) receptor Nakanishi et al, 1990;Sakmann, 1992), the high-affinity KA receptor (Egebjerg et al, 1991) and the N-methyl D-aSpartate (NMDA) receptor (Moriyoshi et al, 1991 ;Kumar et al, 1991 ;Barnard, 1992). Each can exist in many isoforms by combining subunits formed from distinct genes, by alternative splicing or by post-transcriptional modification (Monyer et al, 1991 ;Burnashev et al, 1992).The AMPNKA receptor is responsible for fast information transfer while the NMDA receptor is only operative when the post-synaptic membrane is independently depolarized by another receptor.…”

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confidence: 99%

The glutamatergic nerve terminal

Nicholls

1994

EJB Reviews 1993

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Glutamate as a neurotransmitterThe human brain has about lolo neurones, each of which, on average, makes about 1000 synaptic contacts with other neurones. Of these l O I 3 synapses perhaps up to 90% utilize amino acids as their neurotransmitter. Glutamate is the major excitatory amino acid (acting predominantly on depolarizing post-synaptic receptors) while 4-aminobutyrate (GABA) and glycine are the major inhibitory transmitters (acting on hyper-polarizing receptors). As well as playing the dominant role in fast information transfer, glutamate is of particular interest in view of its involvement in current models of memory and learning (Bliss and Dolphin, 1982;Cotman et al., 1988;Collingridge and Singer, 1990) and because a pathological release of glutamate in brain ischaemia is neurotoxic and a major contributor to the damage caused under these conditions (Rothman and Olney, 1986;Choi, 1988 ;Meldrum and Garthwaite, 1990).A synapse has a pre-synaptic element responsible for the storage and release of transmitter and a post-synaptic element containing one or more classes of receptor for the transmitter. The potent combination of electrophysiology and molecular cloning has allowed a dramatic advance in our understanding of post-synaptic events. Three classes of post-synaptic ionotropic (possessing an integral ion channel) glutamate receptors have been identified and cloned: the 2-amino-3hydroxy-5-methyl-4-isoxazole propionatekainate (AMPA/ KA) receptor Nakanishi et al., 1990;Sakmann, 1992), the high-affinity KA receptor (Egebjerg et al., 1991) and the N-methyl D-aSpartate (NMDA) receptor (Moriyoshi et al., 1991 ;Kumar et al., 1991 ;Barnard, 1992). Each can exist in many isoforms by combining subunits formed from distinct genes, by alternative splicing or by post-transcriptional modification (Monyer et al., 1991 ;Burnashev et al., 1992).The AMPNKA receptor is responsible for fast information transfer while the NMDA receptor is only operative when the post-synaptic membrane is independently depolarized by another receptor. This 'associative' behaviour of the latter is believed to underlie aspects of the learning process.

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Elementary Steps in Synaptic Transmission Revealed by Currents Through Single Ion Channels

Cited by 7 publications

References 54 publications

Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations

Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations

A Molecular Basis for Agonist and Antagonist Actions at GABA_C Receptors

The glutamatergic nerve terminal

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Elementary Steps in Synaptic Transmission Revealed by Currents Through Single Ion Channels

Cited by 7 publications

References 54 publications

Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations

Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations

A Molecular Basis for Agonist and Antagonist Actions at GABAC Receptors

The glutamatergic nerve terminal

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A Molecular Basis for Agonist and Antagonist Actions at GABA_C Receptors