Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice.

The interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the ATF6-DREAM interaction with repaglinide (RP) induced neuroprotection in a model of Huntington's disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis, and death.

IQM-PC332, a Novel DREAM Ligand with Antinociceptive Effect on Peripheral Nerve Injury-Induced Pain.

Neuropathic pain is a form of chronic pain arising from damage of the neural cells that sense, transmit or process sensory information. Given its growing prevalence and common refractoriness to conventional analgesics, the development of new drugs with pain relief effects constitutes a prominent clinical need. In this respect, drugs that reduce activity of sensory neurons by modulating ion channels hold the promise to become effective analgesics.

Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington's disease treatment.

DREAM, a neuronal calcium sensor protein, has multiple cellular roles including the regulation of Ca and protein homeostasis. We recently showed that reduced DREAM expression or blockade of DREAM activity by repaglinide is neuroprotective in Huntington's disease (HD). Here we used structure-based drug design to guide the identification of IQM-PC330, which was more potent and had longer lasting effects than repaglinide to inhibit DREAM in cellular and in vivo HD models.

Phase synchrony in slow cortical potentials is decreased in both expert and trained novice meditators.

Neuronal interactions coupled by phase synchronization have been studied in a wide range of frequency bands, but fluctuations below the delta frequency have often been neglected. In the present study, phase synchrony in slow cortical potentials (SCPs, 0.01-0.

Identification of IQM-266, a Novel DREAM Ligand That Modulates K4 Currents.

Downstream Regulatory Element Antagonist Modulator (DREAM)/KChIP3/calsenilin is a neuronal calcium sensor (NCS) with multiple functions, including the regulation of A-type outward potassium currents ( ). This effect is mediated by the interaction between DREAM and K4 potassium channels and it has been shown that small molecules that bind to DREAM modify channel function. A-type outward potassium current ( ) is responsible of the fast repolarization of neuron action potentials and frequency of firing.

Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis.

Deregulated intracellular Ca and protein homeostasis underlie synaptic dysfunction and are common features in neurodegenerative diseases. DREAM, also known as calsenilin or KChIP-3, is a multifunctional Ca binding protein of the neuronal calcium sensor superfamily with specific functions through protein-DNA and protein-protein interactions. Small-molecules able to bind DREAM, like the anti-diabetic drug repaglinide, disrupt some of the interactions with other proteins and modulate DREAM activity on Kv4 channels or on the processing of activating transcription factor 6 (ATF6).

KChIP3 coupled to Ca oscillations exerts a tonic brake on baseline mucin release in the colon.

Unlabelled: Regulated mucin secretion from specialized goblet cells by exogenous agonist-dependent (stimulated) and -independent (baseline) manner is essential for the function of the epithelial lining. Over extended periods, baseline release of mucin can exceed quantities released by stimulated secretion, yet its regulation remains poorly characterized. We have discovered that ryanodine receptor-dependent intracellular Ca oscillations effect the dissociation of the Ca-binding protein, KChIP3, encoded by gene, from mature mucin-filled secretory granules, allowing for their exocytosis.

Inhibition of DREAM-ATF6 interaction delays onset of cognition deficit in a mouse model of Huntington's disease.

The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a multifunctional neuronal calcium sensor (NCS) that controls Ca and protein homeostasis through gene regulation and protein-protein interactions. Downregulation of DREAM is part of an endogenous neuroprotective mechanism that improves ATF6 (activating transcription factor 6) processing, neuronal survival in the striatum, and motor coordination in R6/2 mice, a model of Huntington's disease (HD). Whether modulation of DREAM activity can also ameliorate cognition deficits in HD mice has not been studied.

Decentering the Self? Reduced Bias in Self- vs. Other-Related Processing in Long-Term Practitioners of Loving-Kindness Meditation.

Research in social neuroscience provides increasing evidence that self and other are interconnected, both on a conceptual and on an affective representational level. Moreover, the ability to recognize the other as "like the self" is thought to be essential for social phenomena like empathy and compassion. Meditation practices such as loving-kindness meditation (LKM) have been found to enhance these capacities.

Specific cytoarchitectureal changes in hippocampal subareas in daDREAM mice.

Background: Transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a Ca(2+)-binding protein that regulates Ca(2+) homeostasis through gene regulation and protein-protein interactions. It has been shown that a dominant active form (daDREAM) is implicated in learning-related synaptic plasticity such as LTP and LTD in the hippocampus. Neuronal spines are reported to play important roles in plasticity and memory.

Transcriptional repressor DREAM regulates trigeminal noxious perception.

Expression of the downstream regulatory element antagonist modulator (DREAM) protein in dorsal root ganglia and spinal cord is related to endogenous control mechanisms of acute and chronic pain. In primary sensory trigeminal neurons, high levels of endogenous DREAM protein are preferentially localized in the nucleus, suggesting a major transcriptional role. Here, we show that transgenic mice expressing a dominant active mutant of DREAM in trigeminal neurons show increased responses following orofacial sensory stimulation, which correlates with a decreased expression of prodynorphin and brain-derived neurotrophic factor in trigeminal ganglia.

Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease.

Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection.

Mindfulness-based Stress Reduction (MBSR) as Treatment for Chronic Back Pain - an Observational Study with Assessment of Thalamocortical Dysrhythmia.

Background: A pilot study of an 8-week mindfulness-based stress reduction (MBSR) program on a sample of low back pain patients was conducted in order to assess the feasibility and effectiveness of the intervention as well as changes in an EEG pattern called thalamocortical dysrhythmia which is associated with chronic pain.

Patients And Methods: 22 patients with chronic low back pain participated in an MBSR program. Effect sizes were measured for psychological functioning, pain severity, and quality of life.

Kcnip1 a Ca²⁺-dependent transcriptional repressor regulates the size of the neural plate in Xenopus.

In amphibian embryos, our previous work has demonstrated that calcium transients occurring in the dorsal ectoderm at the onset of gastrulation are necessary and sufficient to engage the ectodermal cells into a neural fate by inducing neural specific genes. Some of these genes are direct targets of calcium. Here we search for a direct transcriptional mechanism by which calcium signals are acting.

Activation of DREAM (downstream regulatory element antagonistic modulator), a calcium-binding protein, reduces L-DOPA-induced dyskinesias in mice.

Background: Previous studies have implicated the cyclic adenosine monophosphate/protein kinase A pathway as well as FosB and dynorphin-B expression mediated by dopamine D1 receptor stimulation in the development of 3,4-dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia. The magnitude of these molecular changes correlates with the intensity of dyskinesias. The calcium-binding protein downstream regulatory element antagonistic modulator (DREAM) binds to regulatory element sites called DRE in the DNA and represses transcription of target genes such as c-fos, fos-related antigen-2 (fra-2), and prodynorphin.

DREAM controls the on/off switch of specific activity-dependent transcription pathways.

Changes in nuclear Ca(2+) homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K(+) channel interacting protein 3), is a Ca(2+)-binding protein that binds DNA and represses transcription in a Ca(2+)-dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca(2+)-insensitive/CREB-independent dominant active mutant DREAM (daDREAM).

Protein-Protein Interactions: Gene Acronym Redundancies and Current Limitations Precluding Automated Data Integration.

Understanding protein interaction networks and their dynamic changes is a major challenge in modern biology. Currently, several experimental and approaches allow the screening of protein interactors in a large-scale manner. Therefore, the bulk of information on protein interactions deposited in databases and peer-reviewed published literature is constantly growing.

Neuronal Ca(2+) dyshomeostasis in Huntington disease.

The expansion of the N-terminal poly-glutamine tract of the huntingtin (Htt) protein is responsible for Huntington disease (HD). A large number of studies have explored the neuronal phenotype of HD, but the molecular aethiology of the disease is still very poorly understood. This has hampered the development of an appropriate therapeutical strategy to at least alleviate its symptoms.

DREAM mediated regulation of GCM1 in the human placental trophoblast.

The trophoblast transcription factor glial cell missing-1 (GCM1) regulates differentiation of placental cytotrophoblasts into the syncytiotrophoblast layer in contact with maternal blood. Reduced placental expression of GCM1 and abnormal syncytiotrophoblast structure are features of hypertensive disorder of pregnancy--preeclampsia. In-silico techniques identified the calcium-regulated transcriptional repressor--DREAM (Downstream Regulatory Element Antagonist Modulator)--as a candidate for GCM1 gene expression.

The strength of the corticospinal coherence depends on the predictability of modulated isometric forces.

Isometric compensation of predictably frequency-modulated low forces is associated with corticomuscular coherence (CMC) in beta and low gamma range. It remains unclear how the CMC is influenced by unpredictably modulated forces, which create a mismatch between expected and actual sensory feedback. We recorded electroencephalography from the contralateral hand motor area, electromyography (EMG), and the motor performance of 16 subjects during a visuomotor task in which they had to isometrically compensate target forces at 8% of the maximum voluntary contraction with their right index finger.

Roles of CREB in the regulation of FMRP by group I metabotropic glutamate receptors in cingulate cortex.

Background: Fragile X syndrome is caused by lack of fragile X mental retardation protein (FMRP) due to silencing of the FMR1 gene. The metabotropic glutamate receptors (mGluRs) in the central nervous system contribute to higher brain functions including learning/memory, mental disorders and persistent pain. The transcription factor cyclic AMP-responsive element binding protein (CREB) is involved in important neuronal functions, such as synaptic plasticity and neuronal survival.

Is it me or not me? Modulation of perceptual-motor awareness and visuomotor performance by mindfulness meditation.

Background: Attribution of agency involves the ability to distinguish our own actions and their sensory consequences which are self-generated from those generated by external agents. There are several pathological cases in which motor awareness is dramatically impaired. On the other hand, awareness-enhancement practices like tai-chi and yoga are shown to improve perceptual-motor awareness.

Ca2+-dependent transcriptional control of Ca2+ homeostasis.

Intracellular free Ca(2+) ions regulate many cellular functions, and in turn, the cell devotes many genes/proteins to keep tight control of the level of intracellular free Ca(2+). Here, we review recent work on Ca(2+)-dependent mechanisms and effectors that regulate the transcription of genes encoding proteins involved in the maintenance of the homeostasis of Ca(2+) in the cell.