Spillover Transmission Is Mediated by the Excitatory GABA Receptor LGC-35 in<i>C. elegans</i>

Jobson, Meghan A.; Valdez, Chris M.; Gardner, Jann W.; García, L. René; Jørgensen, Erik M.; Beg, Asim A.

doi:10.1523/jneurosci.4557-14.2015

Cited by 29 publications

(57 citation statements)

References 61 publications

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“…This map of metabotropic gene-expression patterns delineates a significant portion of the second messenger communication system in the wiring diagram. In combination with previous work that identified the expression for the ionotropic GABA receptors (Bamber et al, 1999;Beg and Jorgensen, 2003;Gendrel et al, 2016;Jobson et al, 2015), we complete the map of the worm's GABA communication network (all GABA senders and recipients), revealing the surprising conclusion that even though <10% of all neuron classes release GABA, almost all neurons in C. elegans have the capacity to "listen" to GABA. Third, we perform whole-brain activity recordings to assess the nervous system response repertoire to repulsive and attractive stimuli from three distinct modalities: light, gustation, and olfaction.…”

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confidence: 87%

NeuroPAL: A Neuronal Polychromatic Atlas of Landmarks for Whole-Brain Imaging inC. elegans

Yemini

Lin

Nejatbakhsh

et al. 2019

Preprint

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ABSTRACTComprehensively resolving single neurons and their cellular identities from whole-brain fluorescent images is a major challenge. We achieve this in C. elegans through the engineering and use of a multicolor transgene called NeuroPAL (a Neuronal Polychromatic Atlas of Landmarks). NeuroPAL worms share a stereotypical multicolor fluorescence map for the entire hermaphrodite nervous system that allows comprehensive determination of neuronal identities. Neurons labeled with NeuroPAL do not exhibit fluorescence in the green, cyan, or yellow emission channels, allowing the transgene to be used with numerous reporters of gene expression or neuronal dynamics. Here we showcase three studies that leverage NeuroPAL for nervous-system-wide neuronal identification. First, we determine the brainwide expression patterns of all metabotropic receptors for acetylcholine, GABA, and glutamate, completing a map of this communication network. Second, we uncover novel changes in cell fate caused by transcription factor mutations. Third, we record brainwide activity in response to attractive and repulsive chemosensory cues, characterizing multimodal coding and novel neuronal asymmetries for these stimuli. We present a software package that enables semi-automated determination of all neuronal identities based on color and positional information. The NeuroPAL framework and software provide a means to design landmark atlases for other tissues and organisms. In conclusion, we expect NeuroPAL to serve as an invaluable tool for gene expression analysis, neuronal fate studies, and for mapping whole-brain activity patterns.

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confidence: 87%

NeuroPAL: A Neuronal Polychromatic Atlas of Landmarks for Whole-Brain Imaging inC. elegans

Yemini

Lin

Nejatbakhsh

et al. 2019

Preprint

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“…Increasing concentrations of ethanol flatten the amplitude of body‐bending and decreases speed of movement (Davies et al , ). We recently reported that LGC‐35 regulates locomotor body bending and movement speed in C. elegans (Jobson et al , ). Specifically, deletion of LGC‐35 results in exaggerated body bending and increases animals' speed of movement.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike GABA A -ρ receptors, the vast majority of GABA A receptors are hetero-oligomers composed of three distinct subunits, with the (α 1 ) 2 (β 2 ) 2 (γ 2 ) 1 combination being the most abundant in the human brain (Sigel and Steinmann, 2012). Moreover, EXP-1 and LGC-35 are not expressed in the same cells in vivo further supporting that these receptors do not act as hetero-oligomers (Beg and Jorgensen, 2003;Jobson et al, 2015). Second, dose-response relationships reveal that most of the partially folded GABA analogues tested either showed no agonist activity (nipecotic acid, IMA and P4S) or were weak partial agonists (muscimol and isoguvacine) at both EXP-1 and LGC-35.…”

Section: Figurementioning

confidence: 97%

“…single subunit) and bicuculline-insensitive (Bormann, 2000;Chebib and Johnston, 2000). In Caenorhabditis elegans, the ionotropic GABA receptor family consists of chloride-conducting inhibitory (UNC-49) and sodium-conducting excitatory receptors [expulsion defective (EXP-1) and ligand-gated ion channel (LGC-35)] (Bamber et al, 1999;Beg and Jorgensen, 2003;Jobson et al, 2015). Each of these receptors mediate distinct and coordinated neuromuscular contractions.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological characterization of the excitatory ‘Cys‐loop’ GABA receptor family in Caenorhabditis elegans

Nicholl

Jawad

Weymouth³

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEIonotropic GABA receptors are evolutionarily conserved proteins that mediate cellular and network inhibition in both vertebrates and invertebrates. A unique class of excitatory GABA receptors has been identified in several nematode species. Despite wellcharacterized functions in Caenorhabditis elegans, little is known about the pharmacology of the excitatory GABA receptors EXP-1 and LGC-35. Using a panel of compounds that differentially activate and modulate ionotropic GABA receptors, we investigated the agonist binding site and allosteric modulation of EXP-1 and LGC-35. EXPERIMENTAL APPROACHWe used two-electrode voltage clamp recordings to characterize the pharmacological profile of EXP-1 and LGC-35 receptors expressed in Xenopus laevis oocytes. KEY RESULTSThe pharmacology of EXP-1 and LGC-35 is different from that of GABA A and GABA A -ρ receptors. Both nematode receptors are resistant to the competitive orthosteric antagonist bicuculline and to classical ionotropic receptor pore blockers. The GABA A -ρ specific antagonist, TPMPA, was the only compound tested that potently inhibited EXP-1 and LGC-35. Neurosteroids have minimal effects on GABA-induced currents, but ethanol selectively potentiates LGC-35. CONCLUSIONS AND IMPLICATIONSThe pharmacological properties of EXP-1 and LGC-35 more closely resemble the ionotropic GABA A -ρ family. However, EXP-1 and LGC-35 exhibit a unique profile that differs from vertebrate GABA A and GABA A -ρ receptors, insect GABA receptors and nematode GABA receptors. As a pair, EXP-1 and LGC-35 may be utilized to further understand the differential molecular mechanisms of agonist, antagonist and allosteric modulation at ionotropic GABA receptors and may aid in the design of new and more specific anthelmintics that target GABA neurotransmission. AbbreviationsEXP-1, expulsion defective; LGC-35, ligand-gated ion channel

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“…These inconsistencies, along with the fact that many mutations in the charge-selectivity filter region of these channels nearly abolish channel expression (5,8), have led to a confusing picture that becomes increasingly more blurred as new mutational data are added (9,10) and new nonvertebrate genomes are sequenced (e.g., refs. [11][12][13][14][15]. Indeed, although much effort has been devoted to the identification of the mechanism underlying the cation-versus-anion selectivity of these channels, a careful analysis of the literature reveals that a large number of discrepancies exist, that disparate…”

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confidence: 99%

Identifying the elusive link between amino acid sequence and charge selectivity in pentameric ligand-gated ion channels

Cymes

Grosman

2016

Proc. Natl. Acad. Sci. U.S.A.

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Among neurotransmitter-gated ion channels, the superfamily of pentameric ligand-gated ion channels (pLGICs) is unique in that its members display opposite permeant-ion charge selectivities despite sharing the same structural fold. Although much effort has been devoted to the identification of the mechanism underlying the cation-versus-anion selectivity of these channels, a careful analysis of past work reveals that discrepancies exist, that different explanations for the same phenomenon have often been put forth, and that no consensus view has yet been reached. To elucidate the molecular basis of charge selectivity for the superfamily as a whole, we performed extensive mutagenesis and electrophysiological recordings on six different cation-selective and anion-selective homologs from vertebrate, invertebrate, and bacterial origin. We present compelling evidence for the critical involvement of ionized side chains-whether pore-facing or buried-rather than backbone atoms and propose a mechanism whereby not only their charge sign but also their conformation determines charge selectivity. Insertions, deletions, and residue-to-residue mutations involving nonionizable residues in the intracellular end of the pore seem to affect charge selectivity by changing the rotamer preferences of the ionized side chains in the first turn of the M2 α-helices. We also found that, upon neutralization of the charged residues in the first turn of M2, the control of charge selectivity is handed over to the many other ionized side chains that decorate the pore. This explains the long-standing puzzle as to why the neutralization of the intracellular-mouth glutamates affects charge selectivity to markedly different extents in different cation-selective pLGICs.side-chain conformation | electrostatics | patch clamp | electrophysiology | epistasis T he physiological role of a neurotransmitter-gated ion channel (NGIC) depends, to a large extent, on whether it is permeable to cations or anions. In excitable tissues, for example, cationselective NGICs are excitatory because their opening leads to an influx of Na + that depolarizes the cell. Anion-selective NGICs, on the other hand, are mostly inhibitory, but they can also be excitatory depending on a number of factors that include the values of the Cland HCO 3 -equilibrium (Nernst) potentials and the resting membrane potential. Among these ion channels, only the superfamily of pentameric ligand-gated ion channels ("pLGICs") has evolved to give rise to members that are highly selective for either cations or anions while retaining the same overall structure; all other NGICs (that is, those gated by glutamate or ATP) are selective for cations. Thus, because all cation-selective NGICs discriminate poorly between Na + and K + , fast inhibitory synaptic transmission is mediated, exclusively, by the anion-selective pLGICs.Few aspects of pLGICs are as intriguing-and, at the same time, have remained as elusive and controversial-as the physicochemical basis of their opposite charge selectivities. Certainly...

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Spillover Transmission Is Mediated by the Excitatory GABA Receptor LGC-35 inC. elegans

Cited by 29 publications

References 61 publications

NeuroPAL: A Neuronal Polychromatic Atlas of Landmarks for Whole-Brain Imaging inC. elegans

NeuroPAL: A Neuronal Polychromatic Atlas of Landmarks for Whole-Brain Imaging inC. elegans

Pharmacological characterization of the excitatory ‘Cys‐loop’ GABA receptor family in Caenorhabditis elegans

Identifying the elusive link between amino acid sequence and charge selectivity in pentameric ligand-gated ion channels

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