| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hot Topic Review |
1 Neurobiology Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia2 School of Medicine, University of New South Wales, St Vincent's Hospital, Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia3 School of Medicine, University of New South Wales, Kensington, NSW, 2052, Australia
 |
Abstract |
|---|
 Top Abstract IntroductionConclusionsReferences |
|---|
(Received 30 October 2003;
accepted after revision 13 January 2004)
Corresponding author P. R. Schofield: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. Email: p.schofield{at}garvan.org.au
|
Introduction |
|---|
|
TopAbstractIntroductionConclusionsReferences |
|---|
Structure and function of ligand-gated ion channels
The nicotinic-like LGIC superfamily includes the structurally related nicotinic acetylcholine receptor (nAChR), the 
-aminobutyric acid receptor (GABAAR), the glycine receptor (GlyR) and the serotonin type 3 receptor (5-HT3R; Barnard, 1992). The nAChR is involved in fast synaptic transmission between neuronal cells, and at the neuromuscular junction. The GABAA and Gly receptors are involved in inhibition in the central nervous system (CNS), with the GABAAR distributed throughout the CNS and the GlyR predominantly found in the brainstem and spinal cord. The 5-HT3R is found in the central and peripheral nervous system where it modulates neurotransmitter release.
All of the LGICs are comprised of a pentameric arrangement of subunits surrounding a central ion-conducting pore. Each of the subunits of LGIC receptors share a common topology comprised of a large extracellular domain and four transmembrane domains (M1-M4) (Fig. 1). The ligand-binding pocket is formed by structures within the extracellular domain. The M2 domain of each subunit contributes to the lumen of the ion channel, which undergoes a conformational change following ligand-binding to allow the selective permeation of ions. There are two short loops, that connect transmembrane domain M1 to M2 and M2 to M3, a large intracellular loop (M3-M4) and a short carboxy terminus (Grenningloh et al. 1987; Schofield et al. 1987; Betz, 1990).
|
Structure of the extracellular domain
Structural studies of LGIC receptors have been greatly hindered by the absence of a crystal structure. For many years, the most informative structures were of moderate resolution obtained by Unwin and colleagues from electron micrographs of the tightly packed arrays of nAChRs in membranes isolated from the electric organ of Torpedo electric rays. The structure was shown to rotate in the extracellular domain and channel pore between the open and closed states (Unwin, 1993, 1995). The molecular determinants of the rearrangements involved in the conformational changes of the receptor were not well resolved (Unwin, 1993, 1995). It was a challenge to try and combine the structural ‘overview’ provided by the electron micrographs with the large body of information on the ligand-binding domain obtained by techniques such as photo-labelling, protein modification and site-directed mutagenesis. These techniques identified amino acid residues in six discrete locations (binding loops) that formed the ligand-binding pocket of LGICs (Corringer et al. 2000). Adjacent subunits are known to contribute to the binding pocket at the interface, with loop A, loop B and loop C forming the principal component on one subunit, and loop D, loop E and loop F forming the complementary component on the adjacent subunit.
The recent publication of the crystal structure for the acetylcholine binding protein (AChBP; Brejc et al. 2001) has greatly accelerated knowledge within the field by providing the molecular detail of the acetylcholine binding pocket that had previously been lacking. The AChBP is secreted by glial cells surrounding cholinergic synapses in the CNS of the snail Lymnaea stagnalis, and by binding released acetylcholine it is able to modulate cholinergic neurotransmission (Smit et al. 2001). Essentially, the AChBP can be thought of as a soluble extracellular domain of a nAChR, with no ion channel attached (Sixma & Smit, 2003). This protein shows 24% sequence identity with the ligand-binding domain of the 
7 subunit of the nAChR, 20% with other subunits of the AChR and 15–18% with other LGIC receptors (Brejc et al. 2001).
This degree of homology to other members of the LGIC superfamily has been the catalyst to produce theoretical models of extracellular domains for other LGIC receptor superfamily members (Trudell, 2002). These models will allow in-depth studies into the specificity of current pharmacological agents that act on the extracellular domain of various receptors of the LGIC superfamily (Cromer et al. 2002; Trudell & Bertaccini, 2002) and possibly the rational design of new therapeutic compounds.
The interface between two subunits has long been implicated in the assembly of pentameric subunits (Macdonald & Olsen, 1994). Other functional consequences of interface is shown by the requirement of and subunits of the GABAAR to coassemble to create a benzodiazepine binding site, which can be used to modulate receptor function (Cromer et al. 2002). Considering the therapeutic value of benzodiazepines, elucidating the structure between and subunits of the GABAAR may be important in rational drug development. The crystal structure of the AChBP describes the individual residues at the interface that interact in subunit assembly. The residues that contribute to the interface are not well conserved across the LGIC receptor superfamily (Brejc et al. 2001), indicating that they make specific interactions to form pentameric receptors. While the structure of the AChBP gives detail about the binding site and interface of the receptor, this review focuses on the gating mechanisms of the receptor.
Members of the LGIC superfamily contain a signature loop with a conserved disulphide bond in the extracellular domain, the ‘cys-loop’ (Schofield et al. 1987). In the AChBP, the residues in this cys-loop are more hydrophilic than in the membrane-bound receptors (Dougherty & Lester, 2001). It is likely that this allows the AChBP to be a soluble protein enabling the cystallization process, something that is yet to be achieved by expression of the extracellular domains from LGIC receptors. The location of the cys-loop suggests that in LGICs it is likely to interact with the membrane or the transmembrane domains of a functional receptor (Dougherty & Lester, 2001), which is consistent with its hydrophobic nature in LGICs (Fig. 2). Another part of the AChBP, designated as ‘loop 2’ in the crystal structure, was similarly found to be in a position that would be close to the cell membrane in a LGIC. This led to the hypothesis that these two loops may in some way be interacting with perhaps transmembrane domains of the receptor to activate the ion channel (Brejc et al. 2001; Dougherty & Lester, 2001).
|
The crystal structure of the AChBP has also played an important part in determining an high resolution structure using electron micrographs of the nAChR from the Torpedo electric ray (Miyazawa et al. 2003). By mapping the crystal structure of the AChBP to the extracellular domain of the Torpedo nAChR, it was possible to refine the electron densities obtained from the electron micrographs at liquid helium temperatures. The complete Torpedo nAChR sequence could then be threaded on to the refined electron densities to produce a structure for the entire receptor. Of particular interest was the structure of the transmembrane domains that form the channel pore. Previous low-resolution electron micrograph structures of the Torpedo nAChR had indicated a kinked structure in the helical M2 segment of the pore at the conserved leucine L251 in the nAChR (Unwin, 1995). Studies of the AChR pore by the substituted cysteine accessibility method (SCAM) confirmed the kinked helical structure that altered conformation in the transition from open to closed states (Karlin & Akabas, 1995). The conformational change seen in the M2 segment was a rotation during the transition from the closed to the open state that then allows ion permeation through the pore (Unwin, 1995).
This mechanism of rotation of M2 segments to open the channel gate was investigated in the GABAAR. Disulphide bond trapping experiments of substituted cysteine residues at the centre of the M2 segment of the GABAAR showed that the ß1T256C residues of two adjacent ß subunits were able to form disulphide bonds only in the presence of GABA and locked the channel in the open state (Horenstein et al. 2001). This was interpreted as involving an asymmetrical rotation of ß subunits towards each other, possibly with one M2 segment remaining stationary or with both by rotating different amounts. A possible explanation of the relative differences between the ß subunits may arise from the fact that only one of the ß subunits is forming a ligand-binding pocket with an adjacent subunit.
Constitutively active LGIC receptors have been generated by introduced cysteine mutations in the M2 segment of the 5-HT3AR subunits (Panicker et al. 2002). In the light of the results of Horenstein et al. (2001), one interpretation of the mechanism of constitutive activation may be the relative movement of adjacent subunits to allow disulphide bonds between the adjacent cysteines in the channel pore.
The ‘channel gate’ provides a physical impediment to ion flow in the closed state of the receptor and has been shown to be located between hydrophilic residues L251 (a conserved leucine for all LGIC members) and V255 in the Torpedo nAChR structure (Miyazawa et al. 2003). The hydrophobic interactions of the leucine side chain at L251 with the neighbouring side chains and the phenylalanine side chain at F256 with the neighbouring side chains made a tight hydrophobic girdle around the pore (Miyazawa et al. 2003). It is proposed that the rotation of one or two M2 segments weakens the hydrophobic interactions at the girdle, causing all of the M2 segments to rotate and open the channel pore to allow ion permeation.
A linear free energy relationship analysis of mutations within the M2 segment of the nAChR 
subunit indicates there is a change of conformation of the upper half of the M2 segment (above the conserved leucine) which preceeds that of the lower half of the M2 (Cymes et al. 2002). It may be that this conformational change in the upper half of the M2 weakens the hydrophobic interactions, allowing the channel pore to open.
M2–M3 loop linking ligand-binding to channel activation
Naturally occurring and site-directed mutations in the M2–M3 loop for the AChR, GABAAR and GlyR impair channel activation without altering ligand-binding (Baulac et al. 2001; Campos-Caro et al. 1996; Kusama et al. 1994; Lynch et al. 1995; Rajendra et al. 1995). Being located at the extracellular side of the ion channel pore, the M2–M3 loop has been considered to act as a hinge that allows the opening of the channel by rotation of the M2 domain (Lynch et al. 1997), which would be consistent with earlier electron micrograph structures of the nAChR (Unwin, 1995). Conformational changes have been demonstrated in the M2–M3 loop during channel activation. Using methanethiosulphonate reagents to react with substituted cysteines, it was shown that the M2 half of the M2–M3 loop underwent a conformational change associated with channel gating (Lynch et al. 2001). This type of experimental analysis was extended to the GABAAR, where the data suggests that the M2 segment continues two helical turns beyond the lipid membrane boundary and undergoes a conformational change during GABA-induced gating (Bera et al. 2002).
By studying the linear free-energy relationships of various nAChR mutants and using several different agonists, the M2–M3 loop was shown to be an intermediate in the ‘conformational wave’ that is initiated at the ligand-binding site and results in opening of the channel pore at the M2 domains (Grosman et al. 2000). The results indicated that these structures are linked either by a single reaction pathway or by a set of parallel pathways that equally contribute to the conformational change. In this model of the conformational changes associated with channel gating, there is a gap in the structure that might link the ligand-binding pocket and the M2–M3 loop. As described above, the structural information from the AChBP identifies loop 2 and the conserved cys-loop as potential candidates for bridging the gap between the extracellular domain and the M2–M3 loop (Dougherty & Lester, 2001). This became the focus of study for researchers trying to answer this question.
In the GABAAR 1 subunit, the sequence of loop 2 and the cys-loop are rich in negatively charged residues (Kash et al. 2003). The M2–M3 loop contains a positively charged lysine residue, 1K279, which is known to be important in the activation of channel gating (Sigel et al. 1999). The hypothesis was formed that there is an electrostatic interaction between the 1K279 residue in the M2–M3 loop and negatively charged residues of loop 2 or the cys-loop in the extracellular domain of the GABAAR (Kash et al. 2003). By substituting a lysine residue for the aspartic acid residue 1D57 in loop 2 or 1D149 in the cys-loop, Kash and colleagues were able to disrupt channel gating. When the 1K279D mutation was combined with either the 1D57K or 1D149K mutations, the gating defect associated with the single mutations was corrected. Using cross-linking agents they were also able to demonstrate that the 1D57 and 1D149 residues were within 5 Å of the 1K279 residue. Thus, it was demonstrated that direct electrostatic interactions between the M2–M3 loop and loops 2 and the cys-loop, are associated with channel gating in the GABAAR (Kash et al. 2003; Fig. 3).
|
1E53 and 1D57 (in loop 2), and 1K143 and 1D148 (in the cys-loop) are all implicated in channel gating. This was also demonstrated by covalent modification of substituted cysteine residues (Absalom et al. 2003). However, the double-reverse charge mutations did not indicate the same direct electrostatic interactions between the M2–M3 loop and the extracellular domain as seen in the 1 subunit of the GABAAR (Absalom et al. 2003; Schofield et al. 2003).
Inspection of the sequence alignment for the extracellular domains of the GlyR 1 subunit and the GABAAR 1 subunit reveal why this may be the case (Fig. 4). There are fewer negatively charged residues in loop 2 and the cys-loop of the GlyR 1 subunit compared with the GABAAR 1 subunit and they are located in different positions. An alternate molecular interaction to mediate gating may involve hydrogen bonding interactions between polar residues, but this is yet to be tested.
|
1V44) in loop 2 of the extracellular domain and a hydrophobic pocket between residues 1S269 and 1P272 on the M2–M3 loop (Miyazawa et al. 2003). It is thought that a rotation of the subunit caused by ligand-binding results in a 15° clockwise rotation about an axis normal to the membrane plane of the loop containing the 1V44 residue. This interacts with the M2–M3 loop to rotate the M2 transmembrane domain, destabilize the hydrophobic girdle that forms the channel gate and thus allows ions to pass through the pore (Miyazawa et al. 2003).
In all of the LGIC receptors discussed above, it is loop 2 and the cys-loop of the extracellular domain and the M2–M3 loop of the transmembrane domains that are implicated in the signal transduction mechanism. While the fine molecular detail of the interactions between these loop structures would appear to be subtly different between the receptors, there is sufficient commonality to allow for functional chimeric receptors composed of the extracellular domain of the GABAA
1 subunit and the transmembrane domains of the GlyR 1 subunit (Mihic et al. 1997). Similarly, a functional chimera of the 5-HT3AR and nAChR 7 subunits has previously been described (Eisele et al. 1993). Are these chimeras functional because the contributing subunits share sufficient similarity in the loop structure sequences? Are there differences in interaction between other members of the LGIC receptor superfamily? Does this interaction lead to important differences in channel function? No doubt all these questions will be addressed in time.
Subunit heterogeneity
The experimental data reviewed above has focused on interactions within individual subunits of each LGIC receptor that are associated with channel gating. However, there is a great deal of subunit heterogeneity within members of the LGIC receptor superfamily and this heterogeneity has been demonstrated to be necessary for receptor function. Various subunits are involved in determining the assembly, ligand-binding, structural integrity and ion permeation properties of the different LGIC receptors, which has been reviewed elsewhere (Legendre, 2001; Mehta & Ticku, 1999; Reeves & Lummis, 2002; Utkin et al. 2000).
Each subunit within a pentameric LGIC receptor does not necessarily perform an identical function. The binding site of the muscle-type nACh receptor is an excellent example of this. There are two binding sites, located between the and (or 
) subunits and the and subunits, that are nonequivalent (Karlin, 2002). The subunit undergoes a 15–16° rotation of the inner pore facing parts of the subunit to activate channel gating, which does not occur in other subunits (Unwin et al. 2002). The GABAAR binding site can also exhibit differences between subunits. There are residues near the GABA-binding site that impair activation of the GABAAR when introduced into the ß subunit but not the or subunit, indicating that there may also be non-equivalence at the interface of subunits in the GABAAR (Amin & Weiss, 1993).
The channel activation mechanism may not necessarily be the same across the different subunits. When an V132L mutation is introduced in the cys-loop of the subunit of the nAChR, it has a different functional effect to the same mutation in the subunit, while having no effect in other subunits (Shen et al. 2003). This appears to be consistent with the conformational changes in the extracellular domain that are observed in the subunit of the Torpedo nAChR but not the adjacent ß subunit (Unwin et al. 2002). Similarly, the M2–M3 loop performs a different function in different subunits of the GlyR. The M2–M3 loop of the GlyR ß subunit doesn't make the same conformational changes associated with channel gating and mutations in this region don't impair the channel gating mechanism as is the case for the 1 subunit (Shan et al. 2003).
This suggests that, at least in the nAChR and GlyR, it is the subunits that contribute to the ligand-binding pocket which mediate the transition of ligand-binding to activation of channel gating. The conformational changes in the M2 domain of the subunits are then effectively coupled to the M2 segments of the other subunits by hydrophobic interactions within the M2 segment (Miyazawa et al. 2003). This would be an efficient manner to achieve fast channel gating while minimizing the number of molecules that need to be bound (Miyazawa et al. 2003). There is evidence from single channel studies of mutations at the 12' position within the M2 segment of the nAChR subunits that indicate that M2 contributes independently to channel gating. For example, the 12' mutation in the subunit impairs channel gating to a greater degree compared to a similar mutation in the - or ß- subunits (Grosman & Auerbach, 2000).
The common structure shared by LGIC receptors can now be used to identify variances in amino acid residues that lead to functional differences between subunits. As the differences in structure will ultimately determine differences in function, it is necessary to understand receptor structure and variances within it to fully understand receptor function.
|
Conclusions |
|---|
|
TopAbstractIntroductionConclusionsReferences |
|---|
|
References |
|---|
|
TopAbstractIntroductionConclusionsReferences |
|---|
Amin J & Weiss D (1993). GABAA receptor needs two homologous domains of the ß-subunit for activation by GABA but not by pentobarbital. Nature 366, 565–569.[CrossRef][Medline]
Barnard E (1992). Receptor classes and the transmitter-gated ion channels. Trends Biochem Sci 17, 368–374.[CrossRef][Medline]
Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud'homme JF, Baulac M, Brice A, Bruzzone R & LeGuern E (2001). First genetic evidence of GABA (A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet 28, 46–48.[CrossRef][Medline]
Bera AK, Chatav M & Akabas MH (2002). GABAA Receptor M2–M3 Loop Secondary structure and changes in accessibility during channel gating. J Biol Chem 277, 43002–43010.
Betz H (1990). Ligand-gated ion channels in the brain: the amino acid receptor superfamily. Neuron 5, 383–392.[CrossRef][Medline]
Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Oost J, Smit AB & Sixma TK (2001). Crystal structure of an ACh-binding protein that reveals the ligand-binding domain of nicotinic receptors. Nature 411, 269–276.[CrossRef][Medline]
Campos-Caro A, Sala S, Ballesta JJ, Vicente-Agullo F, Criado M & Sala F (1996). A single residue in the M2–M3 loop is a major determinant of coupling between binding and gating in neuronal nicotinic receptors. Proc Natl Acad Sci U S A 93, 6118–6132.
Corringer P-J, Le Novere N & Changeux JP (2000). Nicotinic receptors at the amino acid level. Annu Rev Pharmacol Toxicol 40, 431–458.[CrossRef][Medline]
Cromer BA, Morton CJ & Parker MW (2002). Anxiety over GABA (A) receptor structure relieved by AChBP. Trends Biochem Sci 27, 280–287.[CrossRef][Medline]
Cymes GD, Grosman C & Auerbach A (2002). Structure of the transition state of gating in the acetylcholine receptor channel pore: a phi-value analysis. Biochem 41, 5548–5555.[CrossRef][Medline]
Dougherty DA & Lester HA (2001). Snails, synapses and smokers. Nature 411, 252–255.[Medline]
Eisele J-L, Bertrand S, Galzi J-L, Devillers-Thiery A, Changeux J-P & Bertrand D (1993). Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities. Nature 366, 479–483.[CrossRef][Medline]
Grenningloh G, Reinitz A, Schmitt B, Methfessel C, Zensen M, Beyreuther K, Gundelfinger ED & Betz H (1987). The strychnine-binding subunit of the glycine receptor shows homology with nicotinic acetylcholine receptors. Nature 328, 215–220.[CrossRef][Medline]
Grosman C & Auerbach A (2000). Asymmetric and independent contribution of the second transmembrane segment 12' residues to diliganded gating of acetylcholine receptor channels. J General Physiol 115, 637–651.
Grosman C, Zhou M & Auerbach A (2000). Mapping the conformational wave of acetylcholine receptor channel gating. Nature 403, 773–776.[CrossRef][Medline]
Horenstein J, Wagner DA, Czajkowski C & Akabas MH (2001). Protein mobility and GABA-induced conformational changes in GABAA receptor pore-lining M2 segment. Nat Neurosci 4, 477–485.[Medline]
Karlin A (2002). Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci 3, 102–114.[CrossRef][Medline]
Karlin A & Akabas MH (1995). Towards a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron 15, 1231–1244.[CrossRef][Medline]
Kash TL, Jenkins A, Kelley JC, Trudell JR & Harrison NL (2003). Coupling of agonist binding to channel gating in the GABAA receptor. Nature 421, 272–275.[CrossRef][Medline]
Kusama T, Wang J-B, Spivak CE & Uhl GR (1994). Mutagenesis of the GABA 1 receptor alters agonist affinity and channel gating. Neuroreport 5, 1209–1212.[Medline]
Legendre P (2001). The glycinergic inhibitory synapse. Cell Mol Life Sci 58, 760–793.[CrossRef][Medline]
Lynch JW, Han N-LR, Haddrill J, Pierce KD & Schofield PR (2001). The surface accessibility of the glycine receptor M2–M3 loop is increased in the channel open state. J Neurosci 21, 2589–2599.
Lynch JW, Rajendra S, Barry PH & Schofield PR (1995). Mutations affecting the glycine receptor agonist transduction mechanism convert the competitive antagonist, picrotoxin, into an allosteric potentiator. J Biol Chem 270, 13799–13806.
Lynch JW, Rajendra S, Pierce KD, Handford CA, Barry PH & Schofield PR (1997). Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel. EMBO J 16, 110–120.[CrossRef][Medline]
Macdonald RL & Olsen RW (1994). GABAA receptor channels. Ann Rev Neurosci 17, 569–602.[Medline]
Mehta AK & Ticku MK (1999). An update on GABAA receptors. Brain Res Brain Res Rev 29, 196–217.[CrossRef][Medline]
Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, Harris RA & Harrison NL (1997). Sites of alcohol and volatile anaesthetic action GABAA and glycine receptors. Nature 389, 385–389.[CrossRef][Medline]
Miyazawa A, Fujiyoshi Y & Unwin N (2003). Structure and gating mechanism of the acetylcholine receptor pore. Nature 423, 949–955.[CrossRef][Medline]
Panicker S, Cruz H, Arrabit C & Slesinger PA (2002). Evidence for a centrally located gate in the pore of a serotonin-gated ion channel. J Neurosci 22, 1629–1639.
Rajendra S, Lynch J, Pierce K, French C, Barry P & Schofield P (1995). Mutation of an arginine residue in the human glycine receptor transforms ß-alanine and taurine from agonists into competitive antagonists. Neuron 14, 169–175.[CrossRef][Medline]
Reeves DC & Lummis SC (2002). The molecular basis of the structure and function of the 5-HT3 receptor: a model ligand-gated ion channel. Mol Membr Biol 19, 11–26.[CrossRef][Medline]
Schofield PR, Darlison MG, Fujita N, Burt DR, Stephenson FA, Rodriguez H, Rhee LM, Ramachandran J, Reale V, Glencorse TAVR, Seeburg PH & Barnard EA (1987). Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family. Nature 328, 221–227.[CrossRef][Medline]
Schofield CM, Jenkins A & Harrison NL (2003). A highly conserved aspartic acid residue in the signature disulfide loop of the alpha1 subunit is a determinant of gating in the glycine receptor. J Biol Chem 278, 34079–34083.
Shan Q, Nevin ST, Haddrill JL & Lynch JW (2003). Asymmetric contribution of alpha and beta subunits to the activation of alphabeta heteromeric glycine receptors. J Neurochem 86, 498–507.[CrossRef][Medline]
Shen X-M, Ohno K, Tsujino A, Brengman JM, Gingold M, Sine SM & Engel AG (2003). Mutation causing severe myasthenia reveals functional asymmetry of AChR signature cystine loops in agonist binding and gating. J Clin Invest 11, 497–505.
Sigel E, Buhr A & Baur R (1999). Role of the conserved lysine residue in the middle of the predicted extra-cellular loop between M2 and M3 in the GABA (A) receptor. J Neurochem 73, 1758–1764.[CrossRef][Medline]
Sixma TK & Smit AB (2003). Acetylcholine binding protein (AChBP): a secreted glial protein that provides a high-resolution model for the extracellular domain of pentameric ligand-gated ion channels. Ann Rev Biophys Biomol Struct 32, 311–334.[CrossRef][Medline]
Smit AB, Syed NI, Schapp D, Van Minen J, Klumperman J, Kits S, Lodder H, van der Schors RC, Sorgedrager B, Brejc K, Sixma TK & Garaerts WP (2001). A glia-derived acetylcholine-binding protein that modulates synaptic neurotransmission. Nature 411, 261–268.[CrossRef][Medline]
Trudell J (2002). Unique assignment of inter–subunit association in GABA (A) alpha 1 beta 3 gamma 2 receptors determined by molecular modelling. Biochim Biophys Acta 1565, 91–96.[Medline]
Trudell JR & Bertaccini E (2002). Molecular modelling of specific and non–specific anaesthetic interactions. Br J Anaesth 89, 32–40.
Unwin N (1993). Nicotinic acetylcholine receptor at 9 Å resolution. J Mol Biol 229, 1101–1124.[CrossRef][Medline]
Unwin N (1995). Acetylcholine receptor channel imaged in the open state. Nature 373, 37–43.[CrossRef][Medline]
Unwin N, Miyazawa A, Li J & Fujiyoshi Y (2002). Activation of the nicotinic acetylcholine receptor involves a switch in conformation of the alpha subunits. J Mol Biol 319, 1165–1176.[CrossRef][Medline]
Utkin YN, Tsetlin VI & Hucho F (2000). Structural organization of nicotinic acetylcholine receptors. Membr Cell Biol 13, 143–164.[Medline]
|
Acknowledgements |
|---|
This article has been cited by other articles:
|
|
 |
|
  D. J. Paterson Celebrating 100 years of publishing discovery in physiology 1908 - 2008 Exp Physiol, January 1, 2008; 93(1): 1 - 15. [Full Text] [PDF]
|
|
|
|
 |
|
 X. Cheng, I. Ivanov, H. Wang, S. M. Sine, and J. A. McCammon Nanosecond-Timescale Conformational Dynamics of the Human {alpha}7 Nicotinic Acetylcholine Receptor Biophys. J., October 15, 2007; 93(8): 2622 - 2634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bali and M. H. Akabas The Location of a Closed Channel Gate in the GABAA Receptor Channel J. Gen. Physiol., January 29, 2007; 129(2): 145 - 159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Chen, K. A. Durkin, and J. E. Casida Spontaneous Mobility of GABAA Receptor M2 Extracellular Half Relative to Noncompetitive Antagonist Action J. Biol. Chem., December 15, 2006; 281(50): 38871 - 38878. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Keramidas, T. L. Kash, and N. L. Harrison The pre-M1 segment of the {alpha}1 subunit is a transduction element in the activation of the GABAA receptor J. Physiol., August 15, 2006; 575(1): 11 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, K. Reilly, and Y. Chang Evolutionarily Conserved Allosteric Network in the Cys Loop Family of Ligand-gated Ion Channels Revealed by Statistical Covariance Analyses J. Biol. Chem., June 30, 2006; 281(26): 18184 - 18192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Corry An Energy-Efficient Gating Mechanism in the Acetylcholine Receptor Channel Suggested by Molecular and Brownian Dynamics Biophys. J., February 1, 2006; 90(3): 799 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Grutter, L. P. de Carvalho, V. Dufresne, A. Taly, S. J. Edelstein, and J.-P. Changeux Molecular tuning of fast gating in pentameric ligand-gated ion channels PNAS, December 13, 2005; 102(50): 18207 - 18212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Reeves, M. Jansen, M. Bali, T. Lemster, and M. H. Akabas A Role for the {beta}1-{beta}2 Loop in the Gating of 5-HT3 Receptors J. Neurosci., October 12, 2005; 25(41): 9358 - 9366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Wilkins, A. M. Hosie, and T. G. Smart Proton modulation of recombinant GABAA receptors: influence of GABA concentration and the {beta} subunit TM2-TM3 domain J. Physiol., September 1, 2005; 567(2): 365 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Law, R. H. Henchman, and J. A. McCammon Chemical Theory and Computation Special Feature: A gating mechanism proposed from a simulation of a human {alpha}7 nicotinic acetylcholine receptor PNAS, May 10, 2005; 102(19): 6813 - 6818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Henchman, H.-L. Wang, S. M. Sine, P. Taylor, and J. A. McCammon Ligand-Induced Conformational Change in the {alpha}7 Nicotinic Receptor Ligand Binding Domain Biophys. J., April 1, 2005; 88(4): 2564 - 2576. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
