RIC-3 phosphorylation enables dual regulation of excitation and inhibition of<i>Caenorhabditis elegans</i>muscle

Safdie, Gracia; Liewald, Jana F.; Kagan, Sarah; Battat, Emil; Gottschalk, Alexander; Treinin, Millet

doi:10.1091/mbc.e16-05-0265

Cited by 13 publications

(9 citation statements)

References 36 publications

(72 reference statements)

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“…RIC‐3 Ser164 was shown to be phosphorylated by a casein kinase II homolog, KIN‐10, and dephosphorylated by the calcium calmodulin‐dependent phosphatase, Calcineurin homolog, TAX‐6. Results of this study suggested a role for RIC‐3 phosphorylation in homeostatic control of excitation‐inhibition balance (Safdie et al., 2016).…”

Section: Many Proteins Are Needed To Make Acetylcholine Receptorsmentioning

confidence: 78%

Cholinergic transmission in C. elegans: Functions, diversity, and maturation of ACh‐activated ion channels

Treinin¹,

Jin

2020

Journal of Neurochemistry

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Acetylcholine is an abundant neurotransmitter in all animals. Effects of acetylcholine are excitatory, inhibitory, or modulatory depending on the receptor and cell type. Research using the nematode C. elegans has made ground‐breaking contributions to the mechanistic understanding of cholinergic transmission. Powerful genetic screens for behavioral mutants or for responses to pharmacological reagents identified the core cellular machinery for synaptic transmission. Pharmacological reagents that perturb acetylcholine‐mediated processes led to the discovery and also uncovered the composition and regulators of acetylcholine‐activated channels and receptors. From a combination of electrophysiological and molecular cellular studies, we have gained a profound understanding of cholinergic signaling at the levels of synapses, neural circuits, and animal behaviors. This review will begin with a historical overview, then cover in‐depth current knowledge on acetylcholine‐activated ionotropic receptors, mechanisms regulating their functional expression and their functions in regulating locomotion.

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Section: Many Proteins Are Needed To Make Acetylcholine Receptorsmentioning

confidence: 78%

Cholinergic transmission in C. elegans: Functions, diversity, and maturation of ACh‐activated ion channels

Treinin¹,

Jin

2020

Journal of Neurochemistry

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“…The C. elegans neuromuscular system, where both excitatory (cholinergic) and inhibitory (GABAergic) motor neurons regulate muscle activity, provides a suitable and complementary model for mechanistic studies of E/I imbalance (Stawicki et al, 2011; Safdie et al, 2016; Zhou et al, 2017). In our system, unc-2(zf35gf) mutations led to a modest increase in RAB-3 expression in the neurites of both excitatory and inhibitory motor neurons, consistent with the notion that increased Ca 2+ influx may potentiate the recruitment of synaptic vesicles (Gracheva et al, 2008; Han et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in Caenorhabditis elegans

Huang

Pirri

Rayes

et al. 2019

eLife

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Mutations in pre-synaptic voltage-gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic and decreased GABAergic transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin-dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.

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“…Genes that were upregulated in C. elegans but downregulated in the soleus include those involved in DNA repair (Nsmce1) [63], and the unfolded protein response (Shq1), suggesting increased damage response in C. elegans. Genes that are downregulated in C. elegans but upregulated in the soleus are involved in muscle excitability (Ric3) [64] and synaptic signaling (Syt12, Ric3, Htr7) [64][65][66] which may impact muscle contraction if globally upregulated in neurons. Downregulated in C. elegans were Dpp4, a gene encoding a multi-functional transmembrane protein involved in glucose uptake [67], and Plce1 involved in growth and differentiation [68].…”

Section: Comparison Between C Elegans and Mouse Slow Twitch Muscle Soleusmentioning

confidence: 99%

Mammalian and Invertebrate Models as Complementary Tools for Gaining Mechanistic Insight on Muscle Responses to Spaceflight

Cahill

Cope

Bass

et al. 2021

IJMS

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Bioinformatics approaches have proven useful in understanding biological responses to spaceflight. Spaceflight experiments remain resource intensive and rare. One outstanding issue is how to maximize scientific output from a limited number of omics datasets from traditional animal models including nematodes, fruitfly, and rodents. The utility of omics data from invertebrate models in anticipating mammalian responses to spaceflight has not been fully explored. Hence, we performed comparative analyses of transcriptomes of soleus and extensor digitorum longus (EDL) in mice that underwent 37 days of spaceflight. Results indicate shared stress responses and altered circadian rhythm. EDL showed more robust growth signals and Pde2a downregulation, possibly underlying its resistance to atrophy versus soleus. Spaceflight and hindlimb unloading mice shared differential regulation of proliferation, circadian, and neuronal signaling. Shared gene regulation in muscles of humans on bedrest and space flown rodents suggest targets for mitigating muscle atrophy in space and on Earth. Spaceflight responses of C. elegans were more similar to EDL. Discrete life stages of D. melanogaster have distinct utility in anticipating EDL and soleus responses. In summary, spaceflight leads to shared and discrete molecular responses between muscle types and invertebrate models may augment mechanistic knowledge gained from rodent spaceflight and ground-based studies.

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RIC-3 phosphorylation enables dual regulation of excitation and inhibition ofCaenorhabditis elegansmuscle

Abstract: Excitation–inhibition balance is essential for normal brain function. Calcineurin-dependent dephosphorylation of RIC-3, a chaperone of nicotinic acetylcholine receptors, disinhibits GABAA receptors, enabling fine-tuning of excitation–inhibition balance.

Cited by 13 publications

References 36 publications

Cholinergic transmission in C. elegans: Functions, diversity, and maturation of ACh‐activated ion channels

Cholinergic transmission in C. elegans: Functions, diversity, and maturation of ACh‐activated ion channels

Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in Caenorhabditis elegans

Mammalian and Invertebrate Models as Complementary Tools for Gaining Mechanistic Insight on Muscle Responses to Spaceflight

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