共查询到20条相似文献,搜索用时 31 毫秒
1.
Asymmetric cross-inhibition between GABAA and glycine receptors in rat spinal dorsal horn neurons 总被引:5,自引:0,他引:5
Presynaptic nerve terminals of inhibitory synapses in the dorsal horn of the spinal cord and brain stem can release both GABA and glycine, leading to coactivation of postsynaptic GABAA and glycine receptors. In the present study we have analyzed functional interactions between GABAA and glycine receptors in acutely dissociated neurons from rat sacral dorsal commissural nucleus. Although the application of GABA and glycine activates pharmacologically distinct receptors, the current induced by a simultaneous application of these two transmitters was less than the sum of currents induced by applying two transmitters separately. Sequential application of glycine and GABA revealed that the GABA-evoked current is more affected by glycine than glycine-evoked responses by GABA. Activation of glycine receptors decreased the amplitude and accelerated the rate of desensitization of GABA-induced currents. This asymmetric cross-inhibition is reversible, dependent on the agonist concentration applied, but independent of both membrane potential and intracellular calcium concentration or changes in the chloride equilibrium potential. During sequential applications, the asymmetric cross-inhibition was prevented by selective GABAA or glycine receptor antagonists, suggesting that occupation of binding sites did not suffice to induce glycine and GABAA receptors functional interaction, and receptor channel activation is required. Furthermore, inhibition of phosphatase 2B, but not phosphatase 1 or 2A, prevented GABAA receptor inhibition by glycine receptor activation, whereas inhibition of phosphorylation pathways rendered cross-talk irreversible. Taken together, our results demonstrated that there is an asymmetric cross-inhibition between glycine and GABAA receptors and that a selective modulation of the state of phosphorylation of GABAA receptor and/or mediator proteins underlies the asymmetry in the cross-inhibition. 相似文献
2.
Expression of GABA and glycine receptors by messenger RNAs from the developing rat cerebral cortex 总被引:8,自引:0,他引:8
M K Carpenter I Parker R Miledi 《Proceedings of the Royal Society of London. Series B, Containing papers of a Biological character. Royal Society (Great Britain)》1988,234(1275):159-170
The ontogenesis of mRNAs coding for GABA and glycine receptors in the cerebral cortex of the rat was examined by extracting poly(A)+ mRNA from the brains of embryonic, postnatal or adult rats and injecting it into Xenopus oocytes. The ability of a messenger to express functional receptors was then assayed by measuring the membrane currents elicited by the agonists. The size of the GABA-induced current increased progressively with age, being undetectable in oocytes injected with mRNA from embryonic day 15 and reaching a maximum in oocytes injected with mRNA from postnatal day 30. In contrast, the glycine-induced response was negligible in oocytes injected with mRNA from the cerebral hemispheres of embryos 15 days old; it increased sharply to a maximum with newborn animals and then decreased with age to become very small with mRNA from adult cortex. GABA and glycine receptors induced by mRNA from the cerebral cortex of all ages are associated with chloride channels. 相似文献
3.
Amakhin DB Veselkin NP 《Rossi?skii fiziologicheski? zhurnal imeni I.M. Sechenova / Rossi?skaia akademiia nauk》2011,97(10):1025-1034
The interactions of GABA- and glycine-mediated responses have been analyzed, the whole cell patch-clamp method being used. The response induced by co-application of glycine and GABA was a lesser one than the sum of responses induced by applying two transmitters separately. The molecular mechanisms underlying this effect have been determined. Due to applications of high concentrations of neurotransmitters it was revealed that GABA could activate glycine receptors in frog spinal motoneurons with relatively high efficiency (EC50 = 1.2 mM). The sequential application of neurotransmitters showed that even a single application of glycine could significantly boost the "run-down" of the GABA-mediated current, suggesting that there was a strong phosphorylation-dependent mechanism of GABAa-receptors inhibition. These mechanisms are likely to take place in frog spinal motoneurons when GABA and glycine are co-released from the same synaptic terminal. 相似文献
4.
Responses to GABA, glycine and beta-alanine induced in Xenopus oocytes by messenger RNA from chick and rat brain 总被引:5,自引:0,他引:5
I Parker K Sumikawa R Miledi 《Proceedings of the Royal Society of London. Series B, Containing papers of a Biological character. Royal Society (Great Britain)》1988,233(1271):201-216
Poly (A)+ messenger RNA (mRNA) was extracted from rat and chick brains, and injected into oocytes of Xenopus laevis. This led to the expression of receptors that evoked membrane currents in response to gamma-aminobutyric acid (GABA), glycine and beta-alanine. These currents all inverted at about the chloride equilibrium potential in the oocyte, and showed a marked rectification at negative potentials. Oocytes injected with mRNA from chick optic lobe gave large responses to GABA and beta-alanine, but small responses to glycine. In contrast, one fraction of mRNA from rat cerebral cortex (obtained by sucrose density gradient centrifugation) caused oocytes to develop sensitivity to GABA, glycine and beta-alanine, but very little to GABA. The pharmacological properties of the three amino acid responses also differed. Barbiturate and benzodiazepines potentiated the responses to GABA and beta-alanine, but not to glycine. Strychnine reduced the responses to glycine and beta-alanine, but not to GABA, whereas bicuculline reduced the responses to GABA and beta-alanine, but not to glycine. We conclude that different species of mRNA code for receptors to GABA and glycine, and possibly also for separate beta-alanine receptors. 相似文献
5.
Messenger RNA from bovine retina induces kainate and glycine receptors in Xenopus oocytes 总被引:4,自引:0,他引:4
I Parker K Sumikawa R Miledi 《Proceedings of the Royal Society of London. Series B, Containing papers of a Biological character. Royal Society (Great Britain)》1985,225(1238):99-106
The retina contains several types of nerve cells that communicate through chemical synapses. The transmitter and receptor molecules that mediate signal transmission across these synapses need further characterization. For this purpose, poly (A)+ mRNA was isolated from bovine retinas and injected into Xenopus laevis oocytes. Translation of the foreign mRNA induced the oocyte membrane to acquire functional receptors to kainate and, to a lesser extent, also receptors to glycine, gamma-aminobutryic acid (GABA), aspartate and glutamate. Thus, the cells in the retina must contain different messengers coding for these neurotransmitter receptors. Activation of the kainate receptors opens membrane channels, generating an ionic current which has an equilibrium potential close to 0 mv. The current is well maintained during prolonged application of kainate, and hence these receptors may be involved in the neurotoxic effects produced by kainate in the retina. 相似文献
6.
Desensitization of ligand-gated ion channels plays a critical role for the information transfer between neurons. The current view on γ-aminobutyric acid (GABA)(A) and glycine receptors includes significant rapid components of desensitization as well as cross-desensitization between the two receptor types. Here, we analyze the mechanism of apparent cross-desensitization between native GABA(A) and glycine receptors in rat central neurons and quantify to what extent the current decay in the presence of ligand is a result of desensitization versus changes in intracellular Cl(-) concentration ([Cl(-)](i)). We show that apparent cross-desensitization of currents evoked by GABA and by glycine is caused by changes in [Cl(-)](i). We also show that changes in [Cl(-)](i) are critical for the decay of current in the presence of either GABA or glycine, whereas changes in conductance often play a minor role only. Thus, the currents decayed significantly quicker than the conductances, which decayed with time constants of several seconds and in some cells did not decay below the value at peak current during 20-s agonist application. By taking the cytosolic volume into account and numerically computing the membrane currents and expected changes in [Cl(-)](i), we provide a theoretical framework for the observed effects. Modeling diffusional exchange of Cl(-) between cytosol and patch pipettes, we also show that considerable changes in [Cl(-)](i) may be expected and cause rapidly decaying current components in conventional whole cell or outside-out patch recordings. The findings imply that a reevaluation of the desensitization properties of GABA(A) and glycine receptors is needed. 相似文献
7.
Expression of Neurotransmitter Receptors by mRNAs from Neurons Developing In Vitro: A Xenopus Oocyte Expression Study 总被引:2,自引:2,他引:0
Philip Wahl David Ragsdale Arne Schousboe† Ricardo Miledi 《Journal of neurochemistry》1993,60(1):57-65
Abstract: Poly(A)+ mRNA was extracted from cultures of neurons isolated from mouse embryonic day 14 cerebral cortex and injected into Xenopus oocytes. This led to the expression of receptors for γ-aminobutyric acid (GABA), glycine, acetylcholine, serotonin, glutamate, kainate, N -methyl-D-aspartate, and quisqualate. Northern blot analysis of poly(A)+ mRNA from the cultured neurons with a GluRI cDNA probe revealed the presence of three hybridization bands with estimated mRNA sizes of 5.1, 4.0, and 3.1 kb, respectively. The development of mRNAs coding for neurotransmitter receptors was investigated by isolating mRNA from neurons cultured for 2, 8, and 14 days in vitro and injecting it into Xenopus oocytes. The amplitude of membrane currents elicited by the transmitters gave a measure of the relative amounts of the different mRNAs. The size of the responses to kainate, aspartate (together with glycine), glutamate, acetylcholine, GABA, serotonin, and glycine increased with the time of culture in vitro. However, in contrast to all other agonist-induced currents, the current induced by glycine failed to increase further from 8 to 14 days in culture. It is concluded that the time course of receptor development in cortical neurons in vitro is similar to the development in vivo. 相似文献
8.
Tsvetkov EA Veselkin NP 《Rossi?skii fiziologicheski? zhurnal imeni I.M. Sechenova / Rossi?skaia akademiia nauk》2007,93(7):735-745
Patch-clamp study in the whole multipolar cell (presumably motoneuron) was performed, the cells having been mechanically isolated from the spinal cord of the frog Rana ridibunda. It was shown that GABA and glycine, when applied simultaneously, produced a transmembrane current. Its amplitude was lower than the summed amplitude of currents produced in the same neuron by separate applications of GABA and glycine. The investigation of this occlusion showed that the superfusion of the neurons with solution containing 0.2 mM of glycine totally blocked the responses to GABA (5 mM) application, and vice versa. The crossinhibition can lie in the basis of this phenomenon. It could be due to either the existence of a common receptor complex sensitive to both GABA and glycine or to interaction between GABA and glycine receptors. 相似文献
9.
Kalinina NI Kurchavyĭ GG Amakhin DV Veselkin NP 《Rossi?skii fiziologicheski? zhurnal imeni I.M. Sechenova / Rossi?skaia akademiia nauk》2008,94(9):1005-1016
The membrane potential responses evoked by GABA and glycine bath applications were studied intracellularly in the motoneurons of the isolated frog spinal cord. The amplitude of glycine-evoked responses was 1.5-2.0 larger than that of GABA-evoked response at the same concentration. EC50 were 0.75 mM and 1.57 mM for glycine and GABA, respectively. The amplitude of responses induced by the simultaneous applications of both agonists were 79.1 +/- 2.4% (n = 19) of the sum of individual responses and 130.1 +/- 1.5% (n = 19) of individual glycine-induced responses (partial occlusion). GABA-evoked responses were decreased by 85.3 +/- 0.2% (n = 10) as a result of glycine preliminary application while preapplication of GABA reduced glycine-evoked responses only by 52.9 +/- 0.3% (n = 11). Glycine- and GABA-evoked responses were selectively suppressed by strychnine and bicuculline, respectively. These results suggest that amphibian spinal motoneurones express (less specifically than those of mammals) both glycine (predominantly) and GABAA receptors, with asymmetric cross-inhibition possibly taking place in them. 相似文献
10.
Experiments were carried out on decerebrate cats to identify transsynaptic mediators of spontaneous postsynaptic inhibition of bulbar inspiratory and postinspiratory neurons. Somatic membrane potentials were recorded through the central micropipette of a coaxial multibarreled electrode. Blockers of type A gamma-aminobutyric acid (GABA-A) and glycine receptors were iontophoresed extracellularly from peripheral micropipettes surrounding the central pipette. Effective antagonism was demonstrated by iontophoresis of agonists with antagonists; application of strychnine antagonized the action of glycine but not GABA, and application of bicuculline antagonized the action of GABA but not glycine. In both types of neurons, iontophoresis of either antagonist depolarized the somatic membrane and increased input resistance throughout the respiratory cycle. Bicuculline preferentially depolarized the somatic membrane in both types of neurons during inactive phases. Strychnine increased the firing rate of inspiratory neurons during inspiration despite maintenance of somatic membrane potential at preiontophoresis levels. Tetrodotoxin reduced the effects of iontophoresed bicuculline and strychnine, suggesting that the action of the antagonists required presynaptic axonal conduction. The present results suggest that presynaptic release of both GABA and glycine contributes to tonic postsynaptic inhibition of bulbar respiratory neurons. GABA-A receptors appear to contribute to inhibition during inactive phases in inspiratory and postinspiratory neurons, whereas glycinergic mechanisms appear to contribute to inspiratory inhibition in inspiratory neurons. 相似文献
11.
A distinctive mechanism of cell injury during ATP depletion involves the loss of cellular glycine. The current study examined whether provision of glycine during ATP depletion can prevent injury in PC-12 cells, a cell line with neuronal property. In addition, we have examined the role played by glycine receptors in cytoprotective effects of the amino acid. It was shown that ATP depletion led to plasma membrane damage in PC-12 cells, which was ameliorated by 0.25–5mM glycine. Cytoprotective activity of glycine was shared by alanine, but not by glutamate or -aminobutyric acid (GABA). Of interest, strychnine, an antagonist of glycine receptor, was also protective. The results, while suggesting the involvement of glycine receptor in cytoprotection, indicate that chloride channel activity of the receptor is dispensable. Such a scenario is further supported by the observation that removal of extracellular chloride did not affect ATP depletion–induced cell injury or its prevention by glycine. In short, this study has provided the first evidence for glycine protection of cells with neuronal properties. Cytoprotection may involve the glycine receptor; however, it can be dissociated from its channel activity. 相似文献
12.
Ivic L Sands TT Fishkin N Nakanishi K Kriegstein AR Strømgaard K 《The Journal of biological chemistry》2003,278(49):49279-49285
Glycine and gamma-aminobutyric acid, type A (GABA(A)) receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory synaptic transmission in the adult central nervous system. During development, the activation of these receptors leads to membrane depolarization. Ligands for the two receptors have important implications both in disease therapy and as pharmacological tools. Terpene trilactones (ginkgolides and bilobalide) are unique constituents of Ginkgo biloba extracts that have various effects on the central nervous system. We have investigated the relative potency of these compounds on glycine and GABA(A) receptors. We find that most of the ginkgolides are selective and potent antagonists of the glycine receptor. Bilobalide, the single major component in G. biloba extracts, also reduces glycine-induced currents, although to a lesser extent. Both ginkgolides and bilobalide inhibit GABA(A) receptors, with bilobalide demonstrating a more potent effect. Additionally, we provide evidence that open channels are required for glycine receptor inhibition by ginkgolides. Finally, we employ molecular modeling to elucidate the similarities and differences in the structure of the terpene trilactones to account for the pharmacological properties of these compounds and demonstrate a striking similarity between ginkgolides and picrotoxinin, a GABA(A) and recombinant glycine alpha-homomeric receptor antagonist. 相似文献
13.
gamma-Aminobutyric acid-containing terminals can be apposed to glycine receptors at central synapses 总被引:9,自引:0,他引:9
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The distributions of terminals containing gamma-aminobutyric acid (GABA) and of endings apposed to glycine receptors were investigated cytochemically in the ventral horn of the rat spinal cord. For this purpose, a polyclonal antibody raised to recognize glutamic acid decarboxylase (GAD), a synthetic enzyme for GABA, and three monoclonal antibodies (mAb's) directed against the glycine receptor were used. Double immunofluorescence showed that, surprisingly, GAD-positive terminals are closely associated in this system with glycine receptors at all the investigated cells, most of which were spinal motoneurons. Furthermore, double labeling was performed with immunoenzymatic recognition of GAD and indirect marking of mAb's with colloidal gold. With this combined approach, it was found, at the electron microscopic level, that all GAD-positive terminals are in direct apposition with glycine receptors while, on the other hand, not all glycine receptors are in front of GABA-containing boutons. This result is not due to a cross-reactivity of mAb's with GABA receptors as shown by using as a control synapses known to use GABA as a neurotransmitter in the cerebellar cortex. Indeed, no glycine receptor immunoreactivity was detected on Purkinje cells facing basket axon terminals. However, Purkinje neurons can express glycine receptor immunoreactivity at other synaptic contacts. Assuming that the presence of postsynaptic receptors for glycine indicates that this amino acid is used for neurotransmission at a given synapse, our results strongly support the notion that GABA and glycine, two classical inhibitory transmitters, coexist at some central connections. However, such is not always the case; in the cerebellum, Golgi terminals impinging on the dendrites of granule cells are either GAD-positive or face glycine receptors, in a well-segregated manner. 相似文献
14.
The ocellar L-neurons of cockroach Periplaneta americana were used in the present study as model systems to investigate the pharmacological properties of the GABA receptors. To do so, a glass microelectrode was impaled into the axon of the L-neurons to record the membrane potential intracellularly and to monitor membrane response to GABA treatment and cercal stimulation by air puff. The traditional GABA and their receptor agonists were introduced through perfusion and/or iontophoresis to monitor their effects on the L-neurons. The GABA receptor antagonists were administered by perfusion to examine if the response of the L-neurons to GABA and/or cercal stimulation was changed. The results revealed that administration of GABA, muscimol and imidazole acetic acid, two GABAA agonists, produced depolarization on the L-neurons. However, treatment of 3-APS and guanidine acetic acid, another two GABAA agonists, evoked hyperpolarization on the L-neurons. Among those tested antagonists, only picrotoxin, GABAA antagonist, antagonize the depolarization induced by GABA and/or cercal stimulation. More interestingly, administration of strychnine, glycine receptor antagonist, largely attenuated the depolarization response of the L-neurons to cercal stimulation. This attenuation caused by strychnine was even stronger than that initiated by varied GABA antagonists. In addition, phaclofen, a GABAB receptor antagonist, showed no antagonistic effect. These results strongly suggest that the characteristics of GABA receptors of the ocellar L-neurons may differ from those in vertebrates. It may be more likely to be a novel GABA receptor. 相似文献
15.
Receptors for gamma-aminobutyric acid and voltage-dependent chloride channels as targets for drugs and toxicants 总被引:4,自引:0,他引:4
The function of chloride (Cl-) channel proteins is to regulate the transport of Cl- across membranes. There are two major kinds of Cl- channels: 1) those activated by binding of a transmitter such as gamma-aminobutyric acid (GABA), glycine, or glutamate, and thus are receptors; and 2) those activated by membrane depolarization or by calcium. There are two kinds of GABA receptors: GABAA is the major inhibitory receptor of vertebrate brain and the one that operates a Cl- channel, and the GABAB receptor, which is proposed to regulate cAMP production that is stimulated by other receptors. Except for binding of GABA, these two GABA receptors differ completely in their drug specificities. However, there are many similarities among the GABAA receptor, the glycine receptor, and the voltage-dependent Cl- channel. The two receptors and Cl- channels bind avermectin, whereas bicuculline binds only to mammalian GABAA and glycine receptors, not to the insect brain GABAA receptor. Barbiturates bind to GABAA and voltage-dependent Cl- channels, possibly directly activating them. Benzodiazepines potentiate both the glycine and GABAA receptors. Several insecticides act on the GABAA receptor and voltage-dependent Cl- channel. It is suggested that the GABAA receptor is the primary target for the action of toxaphene and cyclodiene insecticides but a secondary target for lindane and type II pyrethroids. On the other hand, the Cl- channel may be a primary target for avermectin and lindane but a secondary one for cyclodienes. The similarity in certain drug specificities and the operation of Cl- channels suggest a degree of homology between the subunits of GABAA and glycine receptors and the voltage-dependent Cl- channels. 相似文献
16.
Mohammed I Dibas Eric B Gonzales Paromita Das Cathy L Bell-Horner Glenn H Dillon 《The Journal of biological chemistry》2002,277(11):9112-9117
The central nervous system convulsant picrotoxin (PTX) inhibits GABA(A) and glutamate-gated Cl(minus sign) channels in a use-facilitated fashion, whereas PTX inhibition of glycine and GABA(C) receptors displays little or no use-facilitated block. We have identified a residue in the extracellular aspect of the second transmembrane domain that converted picrotoxin inhibition of glycine alpha1 receptors from non-use-facilitated to use-facilitated. In wild type alpha1 receptors, PTX inhibited glycine-gated Cl(minus sign) current in a competitive manner and had equivalent effects on peak and steady-state currents, confirming a lack of use-facilitated block. Mutation of the second transmembrane domain 15'-serine to glutamine (alpha1(S15'Q) receptors) converted the mechanism of PTX blockade from competitive to non-competitive. However, more notable was the fact that in alpha1(S15'Q) receptors, PTX had insignificant effects on peak current amplitude and dramatically enhanced current decay kinetics. Similar results were found in alpha1(S15'N) receptors. The reciprocal mutation in the beta2 subunit of alpha1beta2 GABA(A) receptors (alpha1beta2(N15'S) receptors) decreased the magnitude of use-facilitated PTX inhibition. Our results implicate a specific amino acid at the extracellular aspect of the ion channel in determining use-facilitated characteristics of picrotoxin blockade. Moreover, the data are consistent with the suggestion that picrotoxin may interact with two domains in ligand-gated anion channels. 相似文献
17.
Meier J 《Cell and tissue research》2003,311(3):271-276
The control of synaptic inhibition is crucial for normal brain function. More than 20 years ago, glycine and gamma-aminobutyric acid (GABA) were shown to be the two major inhibitory neurotransmitters. They can be released independently from different terminals or co-released from the same terminal to activate postsynaptic glycine and GABA(A) receptors. The anchoring protein gephyrin is involved in the postsynaptic accumulation of both glycine and GABA(A) receptors. In lower brain regions, both receptors can be concentrated in synapses, whereas in higher brain regions, glycine receptors are mostly excluded from postsynaptic sites. The activation of glycine and/or GABA(A) receptors determines the strength and precise timing of inhibition. Therefore, tight regulation of postsynaptic glycine versus GABA(A) receptor localization is crucial for optimizing synaptic inhibition in neurons. This review focuses on recent findings and discusses questions concerning the specificity of postsynaptic inhibitory neurotransmitter receptor accumulation during inhibitory synapse formation and development. 相似文献
18.
Connolly CN 《Molecular membrane biology》2008,25(4):293-301
The 5-HT(3) and GABA(A) receptors are members of the Cys-loop family of neurotransmitter-gated ion channels that also include receptors for glycine and acetylcholine. The 5-HT(3) and acetylcholine receptors (cationic ion channels) and the GABA(A) and glycine receptors (anionic ion channels) generally depolarize or hyperpolarize, respectively, the neuronal membrane. Within the amino-terminal extracellular region, all members of this family exhibit a similar architecture of ligand binding domains and a number of key residues are completely conserved. The molecular characterization of their ligand binding and gating characteristics has benefited from the existence of a large repertoire of individual subunits that contribute to the pentameric ion channel. Although differences do exist, advances in our knowledge of one member offers valuable insight into the family as a whole. Each member of the Cys-loop receptors (and all other multimeric ion channels) must face the same challenges: How to assemble individual subunits into an ion channel and which subunits to use? How are assembled receptors distinguished from those that are unassembled or misassembled, then exported from the endoplasmic reticulum and delivered to the cell surface? How are they targeted to, and anchored at synaptic and extrasynaptic sites? How and when are they to be removed from these sites to provide long-term regulation of neuronal activity? In this review, we summarize our current knowledge for the 5-HT(3) and GABA(A) receptors that have provided complementary information and helped us build an overall picture of how receptor biogenesis and trafficking occurs. 相似文献
19.
Together, acid-sensing ion channels (ASICs) and epithelial sodium channels (ENaC) constitute the majority of voltage-independent sodium channels in mammals. ENaC is regulated by a chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show that ASICs were reversibly inhibited by activation of GABA(A) receptors in murine hippocampal neurons. This inhibition of ASICs required opening of the chloride channels but occurred with both outward and inward GABA(A) receptor-mediated currents. Moreover, activation of the GABA(A) receptors modified the pharmacological features and kinetic properties of the ASIC currents, including the time course of activation, desensitization and deactivation. Modification of ASICs by open GABA(A) receptors was also observed in both nucleated patches and outside-out patches excised from hippocampal neurons. Interestingly, ASICs and GABA(A) receptors interacted to regulate synaptic plasticity in CA1 hippocampal slices. The activation of glycine receptors, which are similar to GABA(A) receptors, also modified ASICs in spinal neurons. We conclude that GABA(A) receptors and glycine receptors modify ASICs in neurons through mechanisms that require the opening of chloride channels. 相似文献
20.
Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families.To understand how neurons communicate with each other requires a fundamental understanding of neurotransmitter receptor structure and function. Neurotransmitter-gated ion channels, also known as ionotropic receptors, are responsible for fast synaptic transmission. They decode chemical signals into electrical responses, thereby transmitting information from one neuron to another. Their suitability for this important task relies on their ability to respond very rapidly to the transient release of neurotransmitter to affect cell excitability.In the central nervous system (CNS), fast synaptic transmission results in two main effects: neuronal excitation and inhibition. For excitation, the principal neurotransmitter involved is glutamate, which interacts with ionotropic (integral ion channel) and metabotropic (second-messenger signaling) receptors. The ionotropic glutamate receptors are permeable to cations, which directly cause excitation. Acetylcholine and serotonin can also activate specific cation-selective ionotropic receptors to affect neuronal excitation. For controlling cell excitability, inhibition is important, and this is mediated by the neurotransmitters GABA and glycine, causing an increased flux of anions. GABA predominates as the major inhibitory transmitter throughout the CNS, whereas glycine is of greater importance in the spinal cord and brainstem. They both activate specific receptors—for GABA, there are ionotropic and metabotropic receptors, whereas for glycine, only ionotropic receptors are known to date.Together with acetylcholine- and serotonin-gated channels, GABA and glycine ionotropic receptors form the superfamily of Cys-loop receptors, which differs in many aspects from the superfamily of ionotropic glutamate receptors. Over the last two decades, our knowledge of the structure and function of ionotropic receptors has grown rapidly. In this article, we summarize our current understanding of the molecular operation of these receptors and how we can now begin to interpret the role of receptor structure in agonist binding, channel activation, and allosteric modulation of Cys-loop and glutamate receptor families. Further details on the regulation and trafficking of neurotransmitter receptors in synaptic structure and plasticity can be found in accompanying articles. 相似文献