InteractiveFly: GeneBrief

GluClα: Biological Overview | References

BIOLOGICAL OVERVIEW

Sensory systems sequentially extract increasingly complex features. ON and OFF pathways, for example, encode increases or decreases of a stimulus from a common input. This ON/OFF pathway split is thought to occur at individual synaptic connections through a sign-inverting synapse in one of the pathways. This study showed that ON selectivity is a multisynaptic process in the Drosophila visual system. A pharmacogenetics approach demonstrates that both glutamatergic inhibition through GluClα and GABAergic inhibition through Rdl mediate ON responses. Although neurons postsynaptic to the glutamatergic ON pathway input L1 lose all responses in GluClalpha mutants, they are resistant to a cell-type-specific loss of GluClα. This shows that ON selectivity is distributed across multiple synapses, and raises the possibility that cell-type-specific manipulations might reveal similar strategies in other sensory systems. Thus, sensory coding is more distributed than predicted by simple circuit motifs, allowing for robust neural processing (Molina-Obando, 2019).

Animals rely on their sensory systems to process behaviorally relevant information. One common feature of sensory systems is the sequential processing of information to extract complex features from simple inputs. For example, in the visual system, photoreceptors detect light and then downstream neurons progressively extract distinct features, such as contrast, direction of motion, form, or specific objects. Sensory pathways diverge into pathways that become selective for increasingly specific features (Molina-Obando, 2019).

One prominent example is the split into ON and OFF pathways, where individual neurons become selective to either increases (ON) or decreases (OFF) in a signal. Such an ON/OFF dichotomy enables more efficient coding of stimuli in the visual system and occurs across many different species and sensory modalities, such as vision, olfaction, audition, thermosensation, and electrolocation. Examples of how the split into ON and OFF pathways is implemented in sensory information processing have already been described. In the vertebrate retina, ON and OFF pathways split downstream of glutamatergic photoreceptors where ionotropic glutamate receptors on OFF bipolar cells maintain the sign of the response in the OFF pathway, and the metabotropic glutamate receptor mGluR6, located on ON bipolar cells, inverts the sign in the ON pathway. In the olfactory system of C. elegans, an odor response can be split into parallel pathways in which glutamate-gated chloride channels mediate the ON response. While these transformations are thought to occur at specific synapses, connectomics data reveals that neural circuits are intricate and that many of the possible neuronal connections are realized. This argues that important signal transformations might actually be distributed across wider circuit motifs (Molina-Obando, 2019).

In the Drosophila visual system, ON and OFF pathways functionally split in the first order lamina interneurons, but the physiological specialization occurs one synaptic layer further downstream. In brief, information travels from the retina, which houses the photoreceptors, through three optic ganglia: the lamina, the medulla, and the lobula complex, comprising lobula and lobula plate (see Figure 1 at the following site: ON pathway medulla neurons that receive graded, glutamatergic input). Contrast is encoded by the transient response of photoreceptors, and downstream lamina neurons amplify the contrast-sensitive signal component. Then, distinct ON and OFF pathways are required to detect contrast increments and decrements, respectively. In the lamina, L1 is the major input to the ON pathway, whereas L2 and L3 feed into the OFF pathway. The assignment of L1, L2, and L3 to ON and OFF pathways originates from neuronal silencing studies. However, all lamina neurons receiving direct input from photoreceptors depolarize to the offset of light and hyperpolarize to the onset of light, thus passing on information about both ON and OFF. Voltage or calcium signals in most downstream medulla neurons then selectively report only one type of contrast polarity. The major ON pathway medulla neurons Mi1 and Tm3, for example, selectively respond with depolarization or an increase in calcium signal to ON. In the OFF pathway, most neurons instead selectively respond to OFF stimuli, retaining the response polarity of their lamina inputs. Therefore, ON selectivity requires a sign inversion between the L1 input and its postsynaptic partners Mi1 and Tm3. Previous work suggested that the L1 input to the ON pathway is glutamatergic, whereas L2 and L3, the two major inputs to the OFF pathway, are cholinergic. This suggests that glutamate might also be used as an inhibitory neurotransmitter to implement ON/OFF dichotomy in the fly visual system. However, the molecular and cellular mechanisms implementing this signal transformation are not known in Drosophila visual circuitry (Molina-Obando, 2019).

This study has identified the mechanisms underlying splitting of the ON and OFF pathways in the Drosophila visual system. As expected from the major input to the ON pathway being glutamatergic, broad GluClα function is required for all ON responses in medulla neurons or downstream direction-selective cells. However, individual cell types downstream of the glutamatergic L1 input are resilient to a cell-type-specific loss of GluClα, demonstrating that ON selectivity is computed in a distributed manner. This study further showed that both the glutamate-gated chloride channel GluClα and the GABA-gated chloride channel Rdl are widely expressed in the visual system and together mediate ON responses. Thus, ON selectivity is a multisynaptic computation that is established across distributed circuits (Molina-Obando, 2019).

This work shows that visual responses in the first ON-selective neuron of the Drosophila visual system uses a combination of GluClα and Rdl receptors. This reveals a new biophysical mechanism through which ON and OFF pathway dichotomy can be established. While pharmacology can be used to deduce the function of specific molecular mechanisms, these approaches are often not specific to one protein. GluCls and GABARs belong to the same receptor family of ligand-gated chloride channels and have closely related structure and phylogeny. All known noncompetitive antagonists like Picrotoxin, γ-HCH, dieldrin, EBOB and fibronil target both receptor types although the actions are weaker in GluCls compared to GABARs. Along these lines, PTX was thought to affect GABAA receptor at low concentrations, and additionally affect GluCls at high concentrations in vitro and in vivo. This study use of PTX-insensitive alleles for glutamate and GABA-gated chloride channels making possible the deduction that, in vivo, GluClα is already blocked by PTX at lower concentrations than previously thought, and that both GluClα and Rdl play critical roles for ON responses in the Drosophila visual system. These pharmacogenetic experiments using toxin-insensitive alleles prove to be a powerful tool to unambiguously assign specific effects to individual channels (Molina-Obando, 2019).

One benefit of the use of two inhibitory transmitter systems might be the distribution of sensory coding across parallel synapses. GluClα and Rdl also appear to have very different channel dynamics. Interestingly, PTX-insensitive GluClα and Rdl alleles predominantly rescue different aspects of the visual responses. Whereas GluClαS278T predominantly rescued the peak response in all medulla layers, RdlMDRR mainly rescued the plateau response. This is consistent with the results and with previous oocyte recordings revealing that GluClα is fast desensitizing (Cully, 1996). It is also consistent with in vivo recordings of inhibitory glutamate currents in the honeybee. In contrast, GABA receptors stay open throughout the period in which the transmitter is present. Thus, the use of different inhibitory receptors might allow different aspects of a temporally structured stimulus to be encoded. This is consistent with the finding that two different types of inhibition are also in place in the vertebrate retina. There, GABAergic and glycinergic inhibition diversify the response properties of bipolar cells through a direct influence on temporal and spatial features (Molina-Obando, 2019).

While both receptors appear to be broadly expressed in many cell types of the visual system, they could be co-expressed with different transporters and channels, and interact with different molecular partners, further diversifying their role. Another common strategy to generate functional diversity is the bringing together of different receptor subunits with certain homology. Both mammalian GlyR and GABAA receptors can function as hetero-oligomers made up of different subunits and thus generating functional diversity. There are at least three different GluCl subtypes in C. elegans that can be combined. In Drosophila, only one gene coding for a glutamate-gated chloride channel has been identified. Although alternative splicing and post-transcriptional modifications could alter channel function, all known isoforms are identical in their functional domains. However, heteropentameric channels composed of mixed Rdl and GluClα subunits have been suggested biochemically (Ludmerer, 2002). Such a potential presence of hybrid channels might also explain the higher in vivo sensitivity of GluClα to PTX in some cell types. Finally, two distinct inhibitory transmitter systems might be suitable for individual changes during evolution, allowing for adaptation to specific contextual constraints (Molina-Obando, 2019).

The current experiments revealed that GluClα is not exclusively required in a cell-autonomous manner for ON responses, since loss of GluClα function in Mi1 or Tm3 individually does not lead to a loss of ON responses. It is unlikely that this is due to an incomplete loss of function, since independent genetic tools (FlpStop and RNAi) that both disrupted GluClα expression substantially at the mRNA level gave the same result. Furthermore, the same FlpStop allele effectively abolished all ON responses when GluClα function was disrupted within its entire expression pattern. Additionally, a PTX-resistant Rdl channel can mediate ON responses in a PTX background, although L1 is not GABAergic. Together, these results suggest that ON selectivity is not a monosynaptic computation, but that parallel functional pathways can even compensate for the loss of the major synaptic connection that links L1 directly to Mi1 or Tm3. Thus, the emergence of ON selectivity is more distributed than suggested by minimal core circuit motifs. One synaptic layer further downstream, optogenetic activation of Mi1 and Tm3 most strongly contributes to T4/T5 responses. However, the current data further show that T4/T5 neurons still respond to ON stimuli when both Mi1 and Tm3 responses are completely blocked by PTX, arguing that other neurons also significantly contribute to T4/T5 responses under visual stimulation and suggesting that coding is again more distributed at this stage (Molina-Obando, 2019).

Based on connectomics, one can speculate about candidates for the implementation of these parallel circuit motifs between L1 and Mi1 and Tm3. The lamina neuron L5 and the GABAergic feedback neurons C2 and C3 receive L1 inputs and could be part of an interconnected local microcircuit. Intercolumnar neurons, not present in the current connectome datasets, like Pm or Dm neurons, might also be involved and are likely glutamatergic. In fact, there are close to 100 cell types in the visual system and ~60 medulla neurons, but their role is so far unknown. Sensory pathway splits in the periphery are one of the most fundamental steps in sensory processing. Turning this into a process that parallel pathways can achieve might make this important feature extraction step robust to perturbations (Molina-Obando, 2019).

T4 flash responses in a GluClα-deficient background show an increase in calcium signal during the OFF epoch and a decrease during the ON epoch. For a long time, the mechanisms that generate direction-selective responses in T4/T5 neurons were thought to rely on feedforward excitatory mechanisms. Recently, it was suggested that these direction-selective cells in the fly visual system also implement mechanisms that rely on null-direction suppression. Whereas electrophysiological recordings showed inhibition in T4 when the trailing edge of the receptive field was specifically stimulated, whole-cell recording experiments of T4/T5 neurons are daunting and this is the first time that calcium imaging data directly reveals inhibition in response to single ON flashes. Since glutamatergic inhibition via GluClα was disrupted in this experimental context, the data suggests that this is due to GABAergic inhibition. Several neuronal candidates could make inhibitory synapses onto T4 dendrites. Based on connectomics and neurotransmitter identity, neurons like Mi4, C3, CT1 or TmY15 give direct input and are GABAergic (Meier, 2019; Takemura, 2017). Alternatively, this decrease in calcium signal in T4 might come from a lack of excitatory inputs in a GluClα mutant background. Interestingly, Mi1 and Tm3 themselves show inhibition in response to light when GluClα is blocked. However, this effect is more pronounced at their dendrites than in their output layer and shows different kinetics. The current work might thus help uncover a GABAergic inhibitory input to T4 that is more strongly apparent in the absence of Mi1 and Tm3 excitation, and could ultimately reveal the circuit implementation for the inhibitory component of T4/T5 receptive fields. Furthermore, the data also reveals an increase in calcium during OFF stimulation. The major inputs to T4 are themselves rectified. However, rectification in T4 might not be purely inherited by its inputs but also further strengthened at the T4 dendrites. The current findings thus suggest that glutamatergic inhibition contributes to establishing or maintaining contrast selectivity in T4 (Molina-Obando, 2019).

Both GluClα and Rdl are ionotropic ligand-gated receptors. While ionotropic receptors also implement the ON and OFF pathway split in C. elegans chemosensation, examples in vertebrate vision, olfaction and gustation require metabotropic receptors. Ionotropic receptors appear to be more common in insects than in vertebrates. Furthermore, glutamate-gated chloride channels have independently arisen three times within invertebrate clades and are present in arthropods, molluscs and flatworms (Lynagh, 2015), arguing for a strong evolutionary benefit. Ionotropic receptors mediate rapid transduction events at scales smaller than a millisecond, whereas metabotropic ones are in the millisecond to second range and last longer, from seconds to several minutes, due to an enzymatic secondary cascade previous to channel opening. The evolutionary choice of the specific glutamatergic inhibitory system needs to match the sensory processing speed required for accurate behavioral responses in these species. For example, at the photoreceptor level, invertebrate phototransduction is faster than vertebrate phototransduction thanks to sophisticated molecular strategies. Also, the latency of olfactory sensory neurons responses in mammals is longer than that observed in insects. One advantage that metabotropic receptors have over ionotropic receptors is further amplification of the signal. The distributed circuit architecture proposed in this study might therefore strengthen signaling in a system that uses ionotropic signaling (Molina-Obando, 2019).

This study has shown that ON selectivity is not a monosynaptic process as described in other systems. Although acute pharmacological block or a systemic loss of function of GluClα abolished all ON responses in different neurons, cell-type-specific mutants retained intact ON responses, revealing that sensory coding is distributed in the fly visual system. This not only highlights the power of fly genetics but sheds new light onto the mechanisms of ON selectivity in other systems, since conclusions about ON and OFF pathway splits being mediated by specific monosynaptic processes in systems such as the vertebrate retina or the C. elegans chemosensory system relied on systemic loss-of-function approaches. Several of these systems allow for cell-type-specific manipulations using genetic approaches. It will be interesting to revisit these systems and ask if coding is similarly distributed across multiple synapses in different sensory systems and organisms (Molina-Obando, 2019).

Glutamate is an inhibitory neurotransmitter in the Drosophila olfactory system

Glutamatergic neurons are abundant in the Drosophila central nervous system, but their physiological effects are largely unknown. This study investigated the effects of glutamate in the Drosophila antennal lobe, the first relay in the olfactory system and a model circuit for understanding olfactory processing. In the antennal lobe, one-third of local neurons are glutamatergic. Using in vivo whole-cell patch clamp recordings, this study found that many glutamatergic local neurons are broadly tuned to odors. Iontophoresed glutamate hyperpolarizes all major cell types in the antennal lobe, and this effect is blocked by picrotoxin or by transgenic RNAi-mediated knockdown of the GluClα gene, which encodes a glutamate-gated chloride channel. Moreover, antennal lobe neurons are inhibited by selective activation of glutamatergic local neurons using a nonnative genetically encoded cation channel. Finally, transgenic knockdown of GluClα in principal neurons disinhibits the odor responses of these neurons. Thus, glutamate acts as an inhibitory neurotransmitter in the antennal lobe, broadly similar to the role of GABA in this circuit. However, because glutamate release is concentrated between glomeruli, whereas GABA release is concentrated within glomeruli, these neurotransmitters may act on different spatial and temporal scales. Thus, the existence of two parallel inhibitory transmitter systems may increase the range and flexibility of synaptic inhibition (Liu, 2013).

Although glutamatergic neurons are abundant in the Drosophila brain, the role of glutamate as a neurotransmitter in the Drosophila CNS has received little study. In the antennal lobe, where approximately one-third of LNs are glutamatergic, the physiological effects of glutamate have never been characterized. This study shows that glutamate is an inhibitory transmitter that shapes the responses of PNs to olfactory stimuli (Liu, 2013).

In the past, glutamate has been proposed to mediate lateral excitation between olfactory glomeruli. The results of this study demonstrate that the main effect of glutamate is inhibition, not excitation. The possibility cannot be ruled out that glutamate has small excitatory effects, but no evidence was found of excitation even when GluClα was knocked down genetically or inhibited pharmacologically. It is noted that there is in fact lateral excitation in the antennal lobe, which exists in parallel with lateral inhibition. However, lateral excitation is mediated not by glutamate, but by electrical coupling between LNs and PNs (Liu, 2013).

All of the effects of glutamate on PNs were eliminated by knocking down GluClα. The dominant role for GluClα is notable, given how many other glutamate receptors are in the genome. The results are particularly surprising in light of two recent studies that have reported behavioral effects of knocking down an NMDA receptor subunit (NR1) in PNs. Further experiments will be needed to clarify the role of NR1 (Liu, 2013).

There is a precedent for the idea that glutamate can be an inhibitory neurotransmitter in the Drosophila brain. Specifically, several studies have reported that bath-applied glutamate inhibits the large ventrolateral neurons of the Drosophila circadian clock circuit. Collectively, these studies suggest roles for both ionotropic and metabotropic glutamate receptors in glutamatergic inhibition. Regardless of which glutamate receptors are involved, these studies are consistent with the conclusion that glutamate is an important mediator of synaptic inhibition (Liu, 2013).

The idea that glutamate can be inhibitory has important implications for neural coding. One particularly interesting case is the motion vision circuit of the Drosophila optic lobe. Two neuron types, L1 and L2, both receive strong synaptic inputs from photoreceptors, and they respond equally to contrast increments (“on”) and decrements (“off”). However, based on conditional silencing experiments, L1 is thought to provide input to an on pathway, and L2 to an off pathway. Therefore, opponency must arise downstream from L1 and L2. According to recent evidence, L1 is glutamatergic, whereas L2 is cholinergic. In light of the current data, that result suggests that L1 may actually be inhibitory, which would be sufficient to create opponency in the on and off pathways (Liu, 2013).

Glutamate can act as an inhibitory neurotransmitter in the Caenorhabditis elegans olfactory circuit, and this fact too has implications for neural coding of odors in this organism. In the worm, a specific type of glutamatergic olfactory neuron inhibits one postsynaptic neuron via GluCl, while also exciting another postsynaptic neuron via an AMPA-like receptor. This arrangement creates a pair of opponent neural channels that respond in an anticorrelated fashion to odor presentation or odor removal, analogous to opponent channels in the visual system (Liu, 2013).

This study has shown that the cellular actions of Glu-LNs are broadly similar to the actions of GABA-LNs. Specifically, both types of LNs inhibit PNs and other LNs. In addition, both GABA and glutamate inhibit neurotransmitter release from ORNs. Thus, both neurotransmitters inhibit all of the major cell types in the antennal lobe circuit. However, Glu-LNs and GABA-LNs are not functionally identical. In particular, it was found that the vesicular glutamate transporter is mainly confined to the spaces between glomeruli, whereas the vesicular GABA transporter is abundant within glomeruli. This finding implies that glutamate and GABA are released in largely distinct spatial locations. Consistent with this implication, no individual synaptic connections from Glu-LNs onto PNs were found, whereas a substantial rate of connections was found from GABA-LNs onto PNs. Nevertheless, PNs were found to be hyperpolarized by coactivation of multiple Glu-LNs, and PNs are disinhibited by knockdown of GluCl specifically in PNs (Liu, 2013).

These results can be reconciled by a model where the sites of glutamate release are distant from PN glutamate receptors. As a result, glutamate would need to diffuse some distance to inhibit PNs. Coactivation of multiple Glu-LNs would increase extracellular glutamate concentrations, overwhelming uptake mechanisms and allowing glutamate to diffuse further. In this scenario, glutamatergic inhibition should be most important when LN activity is intense and synchronous. By comparison, GABAergic inhibition of PNs does not require LN coactivation, implying a comparatively short distance between presynaptic and postsynaptic sites. There is a precedent in the literature for the idea that different forms of inhibition can be differentially sensitive to LN coactivation, due to the spatial relationship between presynaptic and postsynaptic sites. In the hippocampus, GABA_A receptors are closer than GABA_B receptors to sites of GABA release, and so activation of individual interneurons produces GABA_A but not GABA_B currents, whereas coactivation of many interneurons produces both GABA_A and GABA_B currents (Liu, 2013).

The pharmacology of glutamate-gated conductances in antennal lobe neurons is similar to the pharmacology of GABA_A conductances in these neurons. This result should prompt a reevaluation of studies that used picrotoxin to block inhibition in the antennal lobe. Given the current results, it seems likely that these studies were reducing both glutamatergic and GABAergic inhibition (Liu, 2013).

It is perhaps surprising that knocking down GluClα in PNs had such a substantial effect on PN odor responses, given that picrotoxin alone has comparatively modest effects. The solution to this puzzle may lie in the finding that glutamate regulates not only PNs but also GABA-LNs. Importantly, GABA-LNs are spontaneously active and provide tonic inhibition to PNs. Hence, in the intact circuit, glutamatergic inhibition of GABA-LNs should tend to disinhibit PNs. Picrotoxin prevents Glu-LNs from inhibiting GABA-LNs and should tend to potentiate GABAergic inhibition. The effects of GABA are mediated in part by GABA_B receptors, which are not sensitive to picrotoxin. Thus, picrotoxin likely has bidirectional effects on the total level of inhibition in the circuit. By contrast, knockdown of GluClα specifically in PNs should not directly affect GABA-LNs and should not produce these complex effects. These results illustrate how a cell-specific genetic blockade of a neurotransmitter system can have more dramatic effects than a global pharmacological blockade of the same system (Liu, 2013).

This study reveals that an LN can have push-pull effects on a single population of target cells. For example, Glu-LNs directly inhibit PNs, but they should also disinhibit PNs, via the inhibition of GABA-LNs. This architecture may allow for more robust gain control and rapid transitions between network states and is similar to the wiring of many cortical circuits, where corecruitment of excitation and inhibition is a common motif (Liu, 2013).

Why might the existence of two parallel inhibitory transmitters be useful? The data argue that GABA and glutamate may act on different spatial and temporal scales. Because these two inhibitory systems comprise different cells, receptors, and transporters, they can be modulated independently. Because their properties are encoded by different genes, they can also evolve independently. This organization should confer increased flexibility in adapting synaptic inhibition to a changing environment (Liu, 2013).

Ivermectin and nodulisporic acid receptors in Drosophila melanogaster contain both gamma-aminobutyric acid-gated Rdl and glutamate-gated GluCl alpha chloride channel subunits

35S-labeled derivatives of the insecticides nodulisporic acid and ivermectin were synthesized and demonstrated to bind with high affinity to a population of receptors in Drosophila head membranes that were previously shown to be associated with a glutamate-gated chloride channel. Nodulisporic acid binding was modeled as binding to a single population of receptors. Ivermectin binding was composed of at least two kinetically distinct receptor populations, only one of which was associated with nodulisporic acid binding. The binding of these two ligands was modulated by glutamate, ivermectin, and antagonists of invertebrate gamma-aminobutyric acid (GABA)ergic receptors. Because solubilized nodulisporic acid and ivermectin receptors comigrated as 230-kDa complexes by gel filtration, antisera specific for both the Drosophila glutamate-gated chloride channel subunit GluCl alpha (DmGluCl alpha) and the GABA-gated chloride channel subunit Rdl (DmRdl) proteins were generated and used to examine the possible coassembly of these two subunits within a single receptor complex. DmGluCl alpha antibodies immunoprecipitated all of the ivermectin and nodulisporic acid receptors solubilized by detergent from Drosophila head membranes. DmRdl antibodies also immunoprecipitated all solubilized nodulisporic receptors, but only approximately 70% of the ivermectin receptors. These data suggest that both DmGluCl alpha and DmRdl are components of nodulisporic acid and ivermectin receptors, and that there also exists a distinct class of ivermectin receptors that contains the DmGluCl alpha subunit but not the DmRdl subunit. This co-association of DmGluCl alpha and DmRdl represents the first biochemical and immunological evidence of coassembly of subunits from two different subclasses of ligand-gated ion channel subunits (Ludmerer, 2002).

Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin

The fruit fly Drosophila melanogaster was used to examine the mode of action of the novel insecticide and acaricide nodulisporic acid. Flies resistant to nodulisporic acid were selected by stepwise increasing the dose of drug in the culture media. The resistant strain, glc¹, is at least 20-fold resistant to nodulisporic acid and 3-fold cross-resistant to the parasiticide ivermectin, and exhibited decreased brood size, decreased locomotion, and bang sensitivity. Binding assays using glc¹ head membranes showed a marked decrease in the affinity for nodulisporic acid and ivermectin. A combination of genetics and sequencing identified a proline to serine mutation (P299S) in the gene coding for the glutamate-gated chloride channel subunit DmGluClalpha. To examine the effect of this mutation on the biophysical properties of DmGluClalpha channels, it was introduced into a recombinant DmGluClalpha, and RNA encoding wild-type and mutant subunits was injected into Xenopus oocytes. Nodulisporic acid directly activated wild-type and mutant DmGluClalpha channels. However, mutant channels were approximately 10-fold less sensitive to activation by nodulisporic acid, as well as ivermectin and the endogenous ligand glutamate, providing direct evidence that nodulisporic acid and ivermectin act on DmGluClalpha channels (Kane, 2000).

Search PubMed for articles about Drosophila GluClα

Cully, D. F., Vassilatis, D. K., Liu, K. K., Paress, P. S., Van der Ploeg, L. H., Schaeffer, J. M. and Arena, J. P. (1994). Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature 371(6499): 707-711. PubMed ID: 7935817

Degani-Katzav, N., Gortler, R., Gorodetzki, L. and Paas, Y. (2016). Subunit stoichiometry and arrangement in a heteromeric glutamate-gated chloride channel. Proc Natl Acad Sci U S A 113(5): E644-653. PubMed ID: 26792524

Degani-Katzav, N., Klein, M., Har-Even, M., Gortler, R., Tobi, R. and Paas, Y. (2017a). Trapping of ivermectin by a pentameric ligand-gated ion channel upon open-to-closed isomerization. Sci Rep 7: 42481. PubMed ID: 28218274

Degani-Katzav, N., Gortler, R., Weissman, M. and Paas, Y. (2017b). Mutational analysis at intersubunit interfaces of an anionic glutamate receptor reveals a key interaction important for channel gating by ivermectin. Front Mol Neurosci 10: 92. PubMed ID: 28428744

Kane, N. S., Hirschberg, B., Qian, S., Hunt, D., Thomas, B., Brochu, R., Ludmerer, S. W., Zheng, Y., Smith, M., Arena, J. P., Cohen, C. J., Schmatz, D., Warmke, J. and Cully, D. F. (2000). Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin. Proc Natl Acad Sci U S A 97(25): 13949-13954. PubMed ID: 11095718

Liu, W. W. and Wilson, R. I. (2013). Glutamate is an inhibitory neurotransmitter in the Drosophila olfactory system. Proc Natl Acad Sci U S A 110(25): 10294-10299. PubMed ID: 23729809

Ludmerer, S. W., Warren, V. A., Williams, B. S., Zheng, Y., Hunt, D. C., Ayer, M. B., Wallace, M. A., Chaudhary, A. G., Egan, M. A., Meinke, P. T., Dean, D. C., Garcia, M. L., Cully, D. F. and Smith, M. M. (2002). Ivermectin and nodulisporic acid receptors in Drosophila melanogaster contain both gamma-aminobutyric acid-gated Rdl and glutamate-gated GluCl alpha chloride channel subunits. Biochemistry 41(20): 6548-6560. PubMed ID: 12009920

Lynagh, T., Beech, R. N., Lalande, M. J., Keller, K., Cromer, B. A., Wolstenholme, A. J. and Laube, B. (2015). Molecular basis for convergent evolution of glutamate recognition by pentameric ligand-gated ion channels. Sci Rep 5: 8558. PubMed ID: 25708000

Meier, M. and Borst, A. (2019). Extreme compartmentalization in a Drosophila amacrine cell. Curr Biol 29(9): 1545-1550 e1542. PubMed ID: 31031119

Molina-Obando, S., Vargas-Fique, J. F., Henning, M., Gur, B., Schladt, T. M., Akhtar, J., Berger, T. K. and Silies, M. (2019). ON selectivity in Drosophila vision is a multisynaptic process involving both glutamatergic and GABAergic inhibition. Elife 8. PubMed ID: 31535971

Takemura, S. Y., Nern, A., Chklovskii, D. B., Scheffer, L. K., Rubin, G. M. and Meinertzhagen, I. A. (2017). The comprehensive connectome of a neural substrate for 'ON' motion detection in Drosophila. Elife 6. PubMed ID: 28432786

date revised: 12 November 2019

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