The C. elegans cGMP-Dependent Protein Kinase EGL-4 Regulates Nociceptive Behavioral Sensitivity

Krzyzanowski, Michelle; Brueggemann, Chantal; Ezak, Meredith J.; Wood, John J.; Michaels, Kerry; Jackson, Christopher; Juang, Bi-Tzen; Collins, Kimberly D.; Yu, Michael C.; L’Étoile, Noëlle D.; Ferkey, Denise M.

doi:10.1371/journal.pgen.1003619

Cited by 29 publications

(50 citation statements)

References 112 publications

(177 reference statements)

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“…Candidates for regulation include the ODR-10 receptor itself or G protein regulators such as RGS proteins (Krzyzanowski et al, 2013), in addition to TRPV channels. An early site of desensitization, upstream of the essential voltage-activated calcium channel egl-19 , is also consistent with the weak desensitization when AWA is directly depolarized with Chrimson.…”

Section: Discussionmentioning

confidence: 99%

A Circuit for Gradient Climbing in C. elegans Chemotaxis

Larsch¹,

Flavell²,

Liu³

et al. 2015

Cell Reports

134

195

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Animals have a remarkable ability to track dynamic sensory information. For example, the nematode Caenorhabditis elegans can locate a diacetyl odor source across a 100,000-fold concentration range. Here, we relate neuronal properties, circuit implementation, and behavioral strategies underlying this robust navigation. Diacetyl responses in AWA olfactory neurons are concentration- and history-dependent; AWA integrates over time at low odor concentrations, but as concentrations rise it desensitizes rapidly through a process requiring cilia transport. After desensitization, AWA retains sensitivity to small odor increases. The downstream AIA interneuron amplifies weak odor inputs and desensitizes further, resulting in a stereotyped response to odor increases over three orders of magnitude. The AWA-AIA circuit drives asymmetric behavioral responses to odor increases that facilitate gradient climbing. The adaptation-based circuit motif embodied by AWA and AIA shares computational properties with bacterial chemotaxis and the vertebrate retina, each providing a solution for maintaining sensitivity across a dynamic range.

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Section: Discussionmentioning

confidence: 99%

A Circuit for Gradient Climbing in C. elegans Chemotaxis

Larsch¹,

Flavell²,

Liu³

et al. 2015

Cell Reports

134

195

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“…Initially, N2, egl-4 [encodes the worm PKG gene; homologous to the foraging gene in flies (Krzyzanowski et al 2013; L’Etoile et al 2002)] loss-of-function (LoF; -PKG) and egl-4 gain-of-function (GoF) were explored to determine if PKG plays a role in seizure recovery. After stimulation (3 s, 47 V), worms resumed normal sinusoidal thrashing locomotion.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, there have been other studies investigating both GoF and LoF alleles where LoF appears to differ from the wild-type phenotype, unlike the GoF. In one particular study that investigated C. elegans tastant behavior, the egl-4 LoF allele was more sensitive to an aversive tastant, in this case 1 mM quinine, and the egl-4 GoF was not different from wild-type (Krzyzanowski et al 2013). These findings provide evidence that our results are not out of the ordinary regarding the GoF allele.…”

Section: Discussionmentioning

confidence: 99%

“…A Drosophila melanogaster PKG, encoded by the foraging gene, has two natural allelic variants that have been attributed to many behavioral responses including foraging patterns, egg-laying and neuronal protection during anoxic and hyperthermic stresses (Krzyzanowski et al 2013). Drugs, along with genetics, have been shown to alter the endogenous activity levels of cellular PKG (Dawson-Scully et al 2010).…”

Section: Introductionmentioning

confidence: 99%

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egl-4 modulates electroconvulsive seizure duration in C. elegans

et al. 2018

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Increased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream K+ channels, a mechanism similar to Retigabine, a recently FDA-approved antiepileptic drug. Our results demonstrate that increased PKG activity decreased seizure duration in C. elegans utilizing a recently developed electroconvulsive seizure assay. While the fly is a well-established seizure model, C. elegans are an ideal yet unexploited model which easily uptakes drugs and can be utilized for high-throughput screens. In this study, we show that treating the worms with either a potassium channel opener, Retigabine or published pharmaceuticals that increase PKG activity, significantly reduces seizure recovery times. Our results suggest that PKG signaling modulates downstream K+ channel conductance to control seizure recovery time in C. elegans. Hence, we provide powerful evidence, suggesting that pharmacological manipulation of the PKG signaling cascade may control seizure duration across phyla.

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“…The bimodal Ca 2+ currents that occur in the ASH neuron upon its stimulation are the object of several studies, which explore the connection between Ca 2+ transients, neuronal behavior (6,(23)(24)(25) and synaptic output of the ASH neuron to downstream neurons (10,18,26). In particular, the connection between Ca 2+ transients in the ASH neuron and C. elegans behavior has been the object of several studies that suggest an interesting correlation not only between the "on" response and specific behaviors (27)(28)(29), but also between the "off" response and avoidance behavior (23).…”

Section: Introductionmentioning

confidence: 99%

A mathematical and computational model of the calcium dynamics inCaenorhabditis elegansASH sensory neuro

Mirzakhalili

Epureanu

Gourgou

2017

Preprint

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We propose a mathematical and computational model that captures the stimulusgenerated Ca 2+ transients in the C. elegans ASH sensory neuron. The model is built based on biophysical events and molecular cascades known to unfold as part of neurons' Ca 2+ homeostasis mechanism, as well as on Ca 2+ signaling events. The state of ion channels is described by their probability of being activated or inactivated, and the remaining molecular states are based on biochemically defined kinetic equations with phenomenological adjustments. We estimate the parameters of the model using experimental data of hyperosmotic stimulus-evoked Ca 2+ transients detected with a FRET sensor in young and aged worms, unstressed and exposed to oxidative stress. We use a hybrid optimization method composed of a multi-objective genetic algorithm and nonlinear least-squares to estimate the model parameters. We first obtain the model parameters for young unstressed worms. Next, we use these values of the parameters as a starting point to identify the model parameters for stressed and aged worms. We show that the model, in combination with experimental data, corroborates literature results. In addition, we demonstrate that our model can be used to predict ASH response to complex combinations of stimulation pulses. The proposed model includes for the first time the ASH Ca 2+ dynamics observed during both "on" and "off"responses. This mathematical and computational effort is the first to propose a dynamic model of the Ca 2+ transients' mechanism in C. elegans neurons, based on biochemical pathways of the cell's Ca 2+ homeostasis machinery.Key words: C. elegans, calcium dynamics, ASH neuron, aging, oxidative stress Significance StatementC. elegans is widely used as a model system for monitoring neuronal Ca 2+ transients.The ASH neuron is the subject of several such studies, primarily due to its key importance as a polymodal nociceptor. However, despite its pivotal role in C. elegans biology, and the special characteristics of its stimulus-evoked Ca2 + transients (e.g., the peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/201962 doi: bioRxiv preprint first posted online Oct. 12, 2017; "off" response), no mathematical or computational model has been developed to include special features of ASH Ca 2+ dynamics, i.e. the "off" response. The model includes for the first time the ASH Ca 2+ dynamics observed during both "on" and "off" responses, and is the first to propose a dynamical model of the C. elegans Ca 2+ transients' mechanism based on biochemical pathways of the cell's Ca 2+ homeostasis machinery.

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The C. elegans cGMP-Dependent Protein Kinase EGL-4 Regulates Nociceptive Behavioral Sensitivity

Cited by 29 publications

References 112 publications

A Circuit for Gradient Climbing in C. elegans Chemotaxis

A Circuit for Gradient Climbing in C. elegans Chemotaxis

egl-4 modulates electroconvulsive seizure duration in C. elegans

A mathematical and computational model of the calcium dynamics inCaenorhabditis elegansASH sensory neuro

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