Abstract:
:The neuronal circuit remodels during development as well as in human neuropathologies such as epilepsy. Neurite outgrowth is an obligatory step in these events. We recently reported that alterations in the phosphorylation state of an axon specification/guidance protein, the collapsin response mediator protein 2 (CRMP2), play a major role in the activity-dependent regulation of neurite outgrowth. We also identified (S)-LCM, an inactive stereoisomer of the clinically used antiepileptic drug (R)-LCM (Vimpat®), as a novel tool for preferentially targeting CRMP2-mediated neurite outgrowth. Here, we investigated the mechanism by which (S)-LCM affects CRMP2 phosphorylation by two key kinases, cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK-3β). (S)-LCM application to embryonic cortical neurons resulted in reduced levels of Cdk5- and GSK-3β-phosphorylated CRMP2. Mechanistically, (S)-LCM increased CRMP2 binding to both Cdk5- and GSK-3β without affecting binding of CRMP2 to its canonical partner tubulin. Saturation transfer difference nuclear magnetic resonance (STD NMR) and differential scanning fluorimetry (DSF) experiments demonstrated direct binding of (S)-LCM to CRMP2. Using an in vitro luminescent kinase assay, we observed that (S)-LCM specifically inhibited Cdk5-mediated phosphorylation of CRMP2. Cross-linking experiments and analytical ultracentrifugation showed no effect of (S)-LCM on the oligomerization state of CRMP2. The increased association between Cdk5-phosphorylated CRMP2 and CaV2.2 was reduced by (S)-LCM in vitro and in vivo. This reduction translated into a decrease of calcium influx via CaV2.2 in (S)-LCM-treated neurons compared to controls. (S)-LCM, to our knowledge, is the first molecule described to directly inhibit CRMP2 phosphorylation and may be useful for delineating CRMP2-facilitated functions.
journal_name
Mol Neurobioljournal_title
Molecular neurobiologyauthors
Moutal A,François-Moutal L,Perez-Miller S,Cottier K,Chew LA,Yeon SK,Dai J,Park KD,Khanna M,Khanna Rdoi
10.1007/s12035-015-9141-2subject
Has Abstractpub_date
2016-04-01 00:00:00pages
1959-1976issue
3eissn
0893-7648issn
1559-1182pii
10.1007/s12035-015-9141-2journal_volume
53pub_type
杂志文章abstract::Poly(ADP-ribose) polymerases (PARPs) are enzymes that catalyze the transfer of ADP-ribose units from β-nicotinamide adenine dinucleotide (NAD(+)) to acceptor proteins. PARP-1 is responsible for more than 90 % of protein poly-ADP-ribosylation in the brain and may play a role as a molecular switch for cell survival and ...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/s12035-012-8257-x
更新日期:2012-08-01 00:00:00
abstract::It has recently been reported that the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway regulates neuronal differentiation of neural stem cells (NSCs) derived from rats or mice and is essential for the self-renewal of human embryonic stem cells (hESCs). However, the roles of ...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-015-9325-9
更新日期:2016-08-01 00:00:00
abstract::Early brain injury (EBI), highlighted with inflammation and apoptosis, occurring within 72 h after subarachnoid hemorrhage (SAH), is associated with the prognosis of SAH. Recent studies have revealed that hydrogen-rich saline (HS) exerted multiple neuroprotective properties in many neurological diseases including SAH,...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-015-9242-y
更新日期:2016-07-01 00:00:00
abstract::α-Synuclein, an abundant and conserved presynaptic brain protein, is implicated as a critical factor in Parkinson's disease (PD). The aggregation of α-synuclein is believed to be a critical event in the disease process. α-Synuclein is characterized by a remarkable conformational plasticity, adopting different conforma...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/s12035-014-8818-2
更新日期:2015-01-01 00:00:00
abstract::Structural rearrangements of chromosome 10 are frequently observed in glioblastoma multiforme and over 80 % of tumour samples archived in the catalogue of somatic mutations in cancer database had gene copy number loss for PI4K2A which encodes phosphatidylinositol 4-kinase type IIalpha. PI4K2A loss of heterozygosity mi...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-014-9034-9
更新日期:2016-01-01 00:00:00
abstract::The potassium channel tetramerization domain-containing protein 7 (KCTD7) was named after the structural homology of its predicted N-terminal broad complex, tramtrack and bric à brac/poxvirus and zinc finger domain with the T1 domain of the Kv potassium channel, but its expression profile and cellular function are sti...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-011-8194-0
更新日期:2011-08-01 00:00:00
abstract::Oxidative stress is a key component of the pathological cascade in subarachnoid hemorrhage (SAH). Fucoxanthin (Fx) possesses a strong antioxidant property and has shown neuroprotective effects in acute brain injuries such as ischemic stroke and traumatic brain injury. Here, we investigated the beneficial effects of Fx...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-020-02095-x
更新日期:2020-12-01 00:00:00
abstract::The induction of synthesis or release of endogenous neurotrophic factors in the brain by low-molecular-weight drugs could be a feasible alternative for the direct administration of neurotrophic factors for the treatment of central nervous system disorders. Recent data suggest that several drugs already in clinical use...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1385/MN:29:3:289
更新日期:2004-06-01 00:00:00
abstract::There is considerable attention being given to the association of Alzheimer's disease and cholesterol homeostasis. To that end, some have suggested that elevated cholesterol levels are a risk factor for Alzheimer's disease. If elevated cholesterol is a risk factor for Alzheimer's disease, then it would be expected tha...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1385/MN:31:1-3:185
更新日期:2005-01-01 00:00:00
abstract::Docosahexaenoic acid (DHA) is enriched in membrane phospholipids of the central nervous system (CNS) and has a role in aging and neuropsychiatric disorders. DHA is metabolized by the enzyme Alox15 to 17S-hydroxy-DHA, which is then converted to 7S-hydroperoxy,17S-hydroxy-DHA by a 5-lipoxygenase, and thence via epoxy in...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-017-0413-x
更新日期:2018-02-01 00:00:00
abstract::Alzheimer's disease (AD) and diabetes are among the most common diseases associated with ageing. The pathology of AD is strongly associated with accumulated misfolding proteins that results in neuronal dysfunction within the brain. Diabetes, on the contrary, is characterised by altered insulin signaling that results i...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/s12035-012-8352-z
更新日期:2013-02-01 00:00:00
abstract::Type 2 diabetes (T2D) is a modern socioeconomic burden, mostly due to its long-term complications affecting nearly all tissues. One of them is the brain, whose dysfunctional intracellular quality control mechanisms (namely autophagy) may upregulate apoptosis, leading to cognitive dysfunction and Alzheimer disease (AD)...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-017-0622-3
更新日期:2018-05-01 00:00:00
abstract::Neurodegenerative foldopathies are characterized by aberrant folding of diseased modified proteins, which are major constituents of the intracellular and extracellular lesions. These lesions correlate with the cognitive and/or motor impairment seen in these diseases. The majority of the disease modified proteins in ne...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/s12035-013-8440-8
更新日期:2013-12-01 00:00:00
abstract::Microwave-induced learning and memory deficits in animal models have been gaining attention in recent years, largely because of increasing public concerns on growing environmental influences. The data from our group and others have showed that the injury of mitochondria, the major source of cellular adenosine triphosp...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-014-8667-z
更新日期:2014-12-01 00:00:00
abstract::Antiretroviral therapy (ART) restricts human immunodeficiency virus type one (HIV-1) replication and by so doing, improves the quality and longevity of life for infected people. Nonetheless, treatment can also lead to adverse clinical outcomes such as drug resistance and systemic adverse events. Both could be affected...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-018-1273-8
更新日期:2019-04-01 00:00:00
abstract::Tissue acidosis is a common feature in many pathological conditions. Activation of acid-sensing ion channel 1a (ASIC1a) plays a key role in acidosis-mediated neurotoxicity. Protein kinase C (PKC) activity has been proved to be associated with many physiological processes and pathological conditions; however, whether P...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-020-02056-4
更新日期:2020-11-01 00:00:00
abstract::Prion replication results from the autocatalytic templated assisted conversion of the host-encoded prion protein PrPC into misfolded, polydisperse PrPSc conformers. Structurally distinct PrPSc conformers can give rise to multiple prion strains. Within and between prion strains, the biological activity (replicative eff...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-020-01897-3
更新日期:2020-06-01 00:00:00
abstract::In the developing mammalian, neocortex gap junctions represent a transient, metabolic, and electrical communication system. These gap junctions may play a crucial role during the formation and refinement of neocortical synaptic circuitries. This article focuses on two major points. First, the influence of gap junction...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/BF02755590
更新日期:1996-06-01 00:00:00
abstract::Metals perform important functions in the normal physiological system, and alterations in their levels may lead to a number of diseases. Aluminium (Al) has been implicated as a major risk factor, which is linked to several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. On the other h...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-014-8643-7
更新日期:2014-10-01 00:00:00
abstract::A great deal of attention has been paid to neuroprotective therapies for cerebral ischemic stroke. Our two recent clinical trials showed that ginsenoside Rd (Rd), a kind of monomeric compound extracted from Chinese herbs, Panax ginseng and Panax notoginseng, was safe and efficacious for the treatment of ischemic strok...
journal_title:Molecular neurobiology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s12035-015-9261-8
更新日期:2016-05-01 00:00:00
abstract::Expression changes for long non-coding RNAs (lncRNAs) have been identified in adult glioblastoma multiforme (GBM) and in a mixture of adult and pediatric astrocytoma. Since adult and pediatric astrocytomas are molecularly different, the mixture of both could mask specific features in each. We determined the global exp...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-016-0123-9
更新日期:2017-10-01 00:00:00
abstract::Cannabidiol (CBD), one of the most abundant Cannabis sativa-derived compounds, has been implicated with neuroprotective effect in several human pathologies. Until now, no undesired side effects have been associated with CBD. In this study, we evaluated CBD's neuroprotective effect in terminal differentiation (mature) ...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-014-8843-1
更新日期:2015-08-01 00:00:00
abstract::Following stroke, complete cellular death in the ischemic brain area may ensue, with remaining brain areas undergoing tissue remodelling to various degrees. Experience-dependent brain plasticity exerted through an enriched environment (EE) promotes remodelling after central nervous system injury, such as stroke. Post-...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-017-0461-2
更新日期:2018-03-01 00:00:00
abstract::The retina is an extension of the central nervous system and has been considered to be a simplified, more tractable and accessible version of the brain for a variety of neuroscience investigations. The optic nerve displays changes in response to underlying neurodegenerative diseases, such as stroke, multiple sclerosis...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/s12035-019-01863-8
更新日期:2020-04-01 00:00:00
abstract::The functions of chloride channels in preconditioning-induced cell protection remain unclear. In this report, we show that the volume-activated chloride channels play a key role in hydrogen peroxide (H2O2) preconditioning-induced cell protection in pheochromocytoma PC12 cells. The preconditioning with 100 μM H2O2 for ...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-013-8431-9
更新日期:2013-08-01 00:00:00
abstract::Accumulating evidences indicate that endogenous modulators of excitatory synapses in the mammalian brain are potential targets for treating neuropsychiatric disorders. Indeed, glutamatergic and adenosinergic neurotransmissions were recently highlighted as potential targets for developing innovative anxiolytic drugs. A...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-015-9660-x
更新日期:2017-01-01 00:00:00
abstract::The signaling cascades triggered by neurotrophins such as BDNF and by several neurotransmitters and hormones lead to the rapid induction of gene transcription by increasing the intracellular concentration of cAMP and Ca2+. This review examines the mechanisms by which these second messengers control transcriptional ini...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1385/MN:30:1:091
更新日期:2004-08-01 00:00:00
abstract::There is accumulating evidence on the use of N-acetylcysteine (NAC) in the treatment of patients with neuropsychiatric disorders. As a multi-target drug and a glutathione precursor, NAC is a promising molecule in the management of stress-related disorders, for which there is an expanding field of research investigatin...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-018-1165-y
更新日期:2019-02-01 00:00:00
abstract::Previous studies have demonstrated depressive or hibernation-like roles of phenothiazine neuroleptics [combined chlorpromazine and promethazine (C + P)] in brain activity. This ischemic stroke study aimed to establish neuroprotection by reducing oxidative stress and improving brain metabolism with post-ischemic C + P ...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-016-0280-x
更新日期:2017-12-01 00:00:00
abstract::Depletion of oxygen and glucose even for brief periods is sufficient to cause cerebral ischemia, which is a predominant worldwide cause of motor deficits with the reduction of life quality and subsequently death. Hence, more insights regarding protective measures against ischemic events are becoming a major research g...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-016-0240-5
更新日期:2017-11-01 00:00:00