scholarly journals The sleep gene insomniac ubiquitinates targets at postsynaptic densities and is required for retrograde homeostatic signaling

2018 ◽  
Author(s):  
Koto Kikuma ◽  
Xiling Li ◽  
Sarah Perry ◽  
Qiuling Li ◽  
Pragya Goel ◽  
...  
Keyword(s):  
Synaptic Strength ◽  
Homeostatic Plasticity ◽  
Retrograde Signaling ◽  
Sleep Regulation ◽  
Sleep Behavior ◽  
Receptor Inhibition ◽  
Induction Process ◽  
Ubiquitin Ligase Complex ◽  
Cullin 3 ◽  
Normal Sleep

ABSTRACTThe nervous system confronts challenges during development and experience that can destabilize information processing. To adapt to these perturbations, synapses homeostatically adjust synaptic strength, a process referred to as homeostatic synaptic plasticity. At the Drosophila neuromuscular junction, inhibition of postsynaptic glutamate receptors activates retrograde signaling that precisely increases presynaptic neurotransmitter release to restore baseline synaptic strength. However, the nature of the underlying postsynaptic induction process remains enigmatic. Here, we designed a forward genetic screen to identify factors necessary in the postsynaptic compartment to generate retrograde homeostatic signaling. This approach identified insomniac (inc), a gene that encodes a putative adaptor for the Cullin-3 ubiquitin ligase complex and is essential for normal sleep regulation. Intriguingly, we find that Inc rapidly traffics to postsynaptic densities and is required for increased ubiquitination following acute receptor inhibition. Our study suggests that Inc-dependent ubiquitination, compartmentalized at postsynaptic densities, gates retrograde signaling and provides an intriguing molecular link between the control of sleep behavior and homeostatic plasticity at synapses.

An interleukin-1 receptor fragment inhibits spontaneous sleep and muramyl dipeptide-induced sleep in rabbits

1996 ◽  
Vol 271 (1) ◽  
pp. R101-R108 ◽  
Author(s):  
S. Takahashi ◽  
L. Kapas ◽  
J. Fang ◽  
J. M. Seyer ◽  
Y. Wang ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Interleukin 1 ◽  
Muramyl Dipeptide ◽  
Type I ◽  
Amino Acid Residues ◽  
Central Administration ◽  
Sleep Regulation ◽  
Systemic Injection ◽  
Normal Sleep ◽  
Receptor Fragment

Interleukin-1 (IL-1) is hypothesized to be involved in physiological sleep regulation and in sleep responses occurring during infectious disease. If this hypothesis is correct, then inhibition of endogenous IL-1 should reduce both normal sleep and N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP)-induced sleep. MDP is a somnogenic substance derived from bacterial cell walls. We report here the effects of a synthetic IL-1 receptor fragment corresponding to amino acid residues 86-95 of the human type I IL-1 receptor (IL-1RF) on spontaneous sleep and IL-1 beta- and MDP-induced sleep and fever in rabbits. Two doses of the IL-1RF (25 and 50 micrograms) were injected into normal rabbits intracerebroventricularly (icv). Both doses significantly decreased spontaneous non-rapid eye movement sleep (NREMS) across a 22-h recording period. Pretreatment of rabbits with 25 micrograms of IL-1RF blocked the somnogenic actions of 10 ng icv IL-1. Similarly, central pretreatment of animals with 25 micrograms IL-1RF significantly attenuated the NREMS-promoting and REMS-suppressive actions of 150 pmol MDP injected centrally. The increase in NREMS and decrease in REMS induced by systemic injection of 12.5 micrograms/kg MDP were also significantly suppressed by central administration of 50 micrograms IL-1RF. In contrast, the febrile response induced by either intracerebroventricularly or intravenously injected MDP were not significantly affected by IL-1RF. These results support the hypothesis that endogenous, brain-derived IL-1 contributes to the maintenance of normal sleep and may mediate sleep responses to systemic as well as central bacterial infections.

scholarly journals NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3609
Author(s):  
Holly Robertson ◽  
Albena T. Dinkova-Kostova ◽  
John D. Hayes
Keyword(s):  
Somatic Mutations ◽  
Target Genes ◽  
Cancer Chemoprevention ◽  
Chemical Carcinogenesis ◽  
Related Factor ◽  
Gene Encoding ◽  
Ubiquitin Ligase Complex ◽  
Genes Encoding ◽  
Short Term Adaptation ◽  
Cullin 3

NF-E2 p45-related factor 2 (NRF2, encoded in the human by NFE2L2) mediates short-term adaptation to thiol-reactive stressors. In normal cells, activation of NRF2 by a thiol-reactive stressor helps prevent, for a limited period of time, the initiation of cancer by chemical carcinogens through induction of genes encoding drug-metabolising enzymes. However, in many tumour types, NRF2 is permanently upregulated. In such cases, its overexpressed target genes support the promotion and progression of cancer by suppressing oxidative stress, because they constitutively increase the capacity to scavenge reactive oxygen species (ROS), and they support cell proliferation by increasing ribonucleotide synthesis, serine biosynthesis and autophagy. Herein, we describe cancer chemoprevention and the discovery of the essential role played by NRF2 in orchestrating protection against chemical carcinogenesis. We similarly describe the discoveries of somatic mutations in NFE2L2 and the gene encoding the principal NRF2 repressor, Kelch-like ECH-associated protein 1 (KEAP1) along with that encoding a component of the E3 ubiquitin-ligase complex Cullin 3 (CUL3), which result in permanent activation of NRF2, and the recognition that such mutations occur frequently in many types of cancer. Notably, mutations in NFE2L2, KEAP1 and CUL3 that cause persistent upregulation of NRF2 often co-exist with mutations that activate KRAS and the PI3K-PKB/Akt pathway, suggesting NRF2 supports growth of tumours in which KRAS or PKB/Akt are hyperactive. Besides somatic mutations, NRF2 activation in human tumours can occur by other means, such as alternative splicing that results in a NRF2 protein which lacks the KEAP1-binding domain or overexpression of other KEAP1-binding partners that compete with NRF2. Lastly, as NRF2 upregulation is associated with resistance to cancer chemotherapy and radiotherapy, we describe strategies that might be employed to suppress growth and overcome drug resistance in tumours with overactive NRF2.

scholarly journals Revisiting the NaCl cotransporter regulation by with-no-lysine kinases

2015 ◽  
Vol 308 (10) ◽  
pp. C779-C791 ◽  
Author(s):  
Silvana Bazúa-Valenti ◽  
Gerardo Gamba
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Type Ii ◽  
Complex Issue ◽  
Dark Ages ◽  
Ubiquitin Ligase Complex ◽  
Pseudohypoaldosteronism Type Ii ◽  
Cullin 3 ◽  
Increased Activity ◽  
Pseudohypoaldosteronism Type

The renal thiazide-sensitive Na+-Cl− cotransporter (NCC) is the salt transporter in the distal convoluted tubule. Its activity is fundamental for defining blood pressure levels. Decreased NCC activity is associated with salt-remediable arterial hypotension with hypokalemia (Gitelman disease), while increased activity results in salt-sensitive arterial hypertension with hyperkalemia (pseudohypoaldosteronism type II; PHAII). The discovery of four different genes causing PHAII revealed a complex multiprotein system that regulates the activity of NCC. Two genes encode for with-no-lysine (K) kinases WNK1 and WNK4, while two encode for kelch-like 3 (KLHL3) and cullin 3 (CUL3) proteins that form a RING type E3 ubiquitin ligase complex. Extensive research has shown that WNK1 and WNK4 are the targets for the KLHL3-CUL3 complex and that WNKs modulate the activity of NCC by means of intermediary Ste20-type kinases known as SPAK or OSR1. The understanding of the effect of WNKs on NCC is a complex issue, but recent evidence discussed in this review suggests that we could be reaching the end of the dark ages regarding this matter.

Sleep Behavior and Sleep Regulation from Infancy Through Adolescence

2012 ◽  
Vol 7 (3) ◽  
pp. 529-538 ◽  
Author(s):  
Oskar G. Jenni ◽  
Mary A. Carskadon
Keyword(s):  
Sleep Regulation ◽  
Sleep Behavior

scholarly journals Fxr1 regulates sleep and synaptic homeostasis

2019 ◽  
Author(s):  
Jivan Khlghatyan ◽  
Alesya Evstratova ◽  
Lusine Bozoyan ◽  
Simon Chamberland ◽  
Aleksandra Marakhovskaia ◽  
...  
Keyword(s):  
Sleep Deprivation ◽  
Fragile X ◽  
Synaptic Strength ◽  
Homeostatic Plasticity ◽  
System Level ◽  
Synaptic Homeostasis ◽  
Brain Functions ◽  
Sleep Homeostasis ◽  
Autosomal Homolog ◽  
Dependent Mechanism

AbstractThe fragile X autosomal homolog 1 (Fxr1) has been GWAS-associated to schizophrenia and insomnia but its contributions to brain functions are unclear. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and engages both global and cell autonomous level processes. We used Crispr/Cas9-mediated somatic knockouts, overexpression, neuronal activity recordings and translatome sequencing, to examine the contribution of Fxr1 to cell-autonomous homeostatic synaptic scaling and global-level sleep homeostasis. Our findings indicate that Fxr1 is downregulated during scaling and sleep deprivation via a Gsk3β dependent mechanism. In both conditions, downregulation of Fxr1 is essential for the homeostatic modulation of synaptic strength. Furthermore, overexpression of Fxr1 during sleep deprivation results in altered EEG signatures and reverts changes of translatome profiles. These findings indicate that Fxr1 represents a shared signaling hub linking cell autonomous homeostatic plasticity and system level sleep homeostasis with potential implications for neuropsychiatric illnesses.

scholarly journals Effects of (±) 3,4-Methylenedioxymethamphetamine (MDMA) on Sleep and Circadian Rhythms

2007 ◽  
Vol 7 ◽  
pp. 231-238 ◽  
Author(s):  
Una D. McCann ◽  
George A. Ricaurte
Keyword(s):  
Circadian Rhythms ◽  
Animal Species ◽  
Future Research ◽  
Sleep Regulation ◽  
Wake Patterns ◽  
Normal Sleep ◽  
Memory Disturbance ◽  
Monoaminergic Neurons ◽  
Preclinical And Clinical Studies ◽  
Circadian Patterns

Abuse of stimulant drugs invariably leads to a disruption in sleep-wake patterns by virtue of the arousing and sleep-preventing effects of these drugs. Certain stimulants, such as 3,4-methylenedioxymethamphetamine (MDMA), may also have the potential to produce persistent alterations in circadian regulation and sleep because they can be neurotoxic toward brain monoaminergic neurons involved in normal sleep regulation. In particular, MDMA has been found to damage brain serotonin (5-HT) neurons in a variety of animal species, including nonhuman primates, with growing evidence that humans are also susceptible to MDMA-induced brain 5-HT neurotoxicity. 5-HT is an important modulator of sleep and circadian rhythms and, therefore, individuals who sustain MDMA-induced 5-HT neurotoxicity may be at risk for developing chronic abnormalities in sleep and circadian patterns. In turn, such abnormalities could play a significant role in other alterations reported in abstinent in MDMA users (e.g., memory disturbance). This paper will review preclinical and clinical studies that have explored the effects of prior MDMA exposure on sleep, circadian activity, and the circadian pacemaker, and will highlight current gaps in knowledge and suggest areas for future research.

Conceptualization and Psychometric Properties of the Sleep Behavior Self-regulation Dimensions: A Theory-Based Instrument

2021 ◽  
Author(s):  
parvin ghasemi ◽  
Ahmad Ali Eslami ◽  
Maryam Amidi Mazaheri
Keyword(s):  
Item Analysis ◽  
Self Regulation ◽  
Measurement Instrument ◽  
Psychometric Evaluation ◽  
Influential Factors ◽  
Test Reliability ◽  
Sleep Regulation ◽  
Sleep Behavior ◽  
Student Sample ◽  
Education Performance

Abstract Background: Focus on sleep regulation is crucial due to the direct health consequences of insufficient sleep to adolescents’ health and education performance. This study aims to develop and validate an instrument to measure sleep behavior self-regulation (SBSR) and its influential factors in a student sample.Methods: A preliminary version of the measurement instrument was developed using a literature review and conceptual framework. Expert analysis of content validity, item analysis, factor analysis and reliability analysis was performed for the psychometric evaluation. This study has a total of 401 students. The data was analyzed using SPSS 22.0 and AMOS 22.0.Results: The exploratory factor analyses offered a structure with six factors. The model presents a good fit (χ2/df = 1.65, RMSEA = 0.053, CFI = 0.920, and GFI =0.826). General test reliability was good (α = 0.9).Conclusions: SBSRI is a multidimensional instrument and a valid and reliable way of obtaining information about sleep behavior self-regulation. The use of this instrument will make it possible to adjust behavior to subjective goals and real experiences to promote sleep-related behavior change.

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