A5015100317- Neuroscience and Neuropharmacology Research
- Ion channel regulation and function
- Mitochondrial Function and Pathology
- Genetic Neurodegenerative Diseases
- Neuroscience and Neural Engineering
- Protein Kinase Regulation and GTPase Signaling
- Signaling Pathways in Disease
- Ubiquitin and proteasome pathways
- Phosphodiesterase function and regulation
- Genetics and Neurodevelopmental Disorders
- Folate and B Vitamins Research
- Retinal Development and Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Calcium signaling and nucleotide metabolism
- Muscle Physiology and Disorders
- DNA Repair Mechanisms
- Metalloenzymes and iron-sulfur proteins
- Cellular transport and secretion
Pfizer (United States)
2022-2023
Vanderbilt University
2016-2023
Institute of Molecular Biology and Biophysics
2017-2020
Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding underlying pathophysiological mechanisms. Here we show that de novo Glu183 Val (E183V) mutation in CaMKIIα catalytic domain, identified proband diagnosed with ASD, decreases both substrate phosphorylation and regulatory autophosphorylation, mutated kinase acts dominant-negative manner reduce CaMKIIα-WT autophosphorylation. The E183V also reduces binding...
Friedreich's ataxia is a rare disorder resulting from deficiency of frataxin, mitochondrial protein implicated in the synthesis iron-sulfur clusters. Preclinical studies mice have shown that gene therapy promising approach to treat individuals with ataxia. However, recent report provided evidence AAVrh10-mediated overexpression frataxin could lead cardiotoxicity associated dysfunction. While evaluating an AAV9-based using chicken β-actin promoter, we showed toxic be reached mouse liver and...
The activation of neuronal plasma membrane Ca2+ channels stimulates many intracellular responses. Scaffolding proteins can preferentially couple specific to distinct downstream outputs, such as increased gene expression, but the molecular mechanisms that underlie exquisite specificity these signaling pathways are incompletely understood. Here, we show complexes containing CaMKII and Shank3, a postsynaptic scaffolding protein known interact with L-type calcium (LTCCs), be specifically...
Neuronal excitation can induce new mRNA transcription, a phenomenon called excitation–transcription (E-T) coupling. Among several pathways implicated in E-T coupling, activation of voltage-gated L-type Ca2+ channels (LTCCs) the plasma membrane initiate signaling pathway that ultimately increases nuclear CREB phosphorylation and, most cases, expression immediate early genes. Initiation this long-range has been shown to require recruitment Ca2+-sensitive enzymes nanodomain vicinity LTCC by an...
Abstract Clustering of L‐type voltage‐gated Ca 2+ channels (LTCCs) in the plasma membrane is increasingly implicated creating highly localized signaling nanodomains. For example, neuronal LTCC activation can increase phosphorylation nuclear CREB transcription factor by increasing concentrations within a nanodomain close to channel, without requiring bulk increases cytosol or nucleus. However, molecular basis for clustering poorly understood. The postsynaptic scaffolding protein Shank3...
Iron–sulfur clusters (Fe–S or ISC) are essential cofactors that function in a wide range of biological pathways. In mammalian cells, Fe–S biosynthesis primarily relies on mitochondria and involves concerted group evolutionary-conserved proteins forming the ISC pathway. early stage pathway, core complex is required for de novo assembly Fe–S. humans, comprises cysteine desulfurase NFS1, scaffold protein ISCU2, frataxin (FXN), ferredoxin FDX2, regulatory/accessory ISD11 Acyl Carrier Protein...
Abstract Ca 2+ /calmodulin-dependent protein kinase 2 (CAMK2) plays a critical role in calcium signaling. Recent gene knockout studies show that CAMK2A and CAMK2B can have distinct roles yet also partially compensate for each other unknown brain functions. In order to provide insight into potential novel CAMK2 functions, we performed parallel phosphoproteomic analyses on non-stimulated cortex tissue from inducible Camk2a Camk2b double ( f/f ;Camk2b ;CAG-Cre ESR ) mice wild type mice. A total...
Friedreich's ataxia (FA) is an autosomal recessive disorder caused by a deficiency in frataxin (FXN), mitochondrial protein that plays critical role the synthesis of iron sulfur clusters (Fe-S), vital inorganic cofactors necessary for numerous cellular processes. FA characterized progressive and hypertrophic cardiomyopathy, with cardiac dysfunction as most common cause mortality patients. Commonly used cardiac-specific mouse models utilize muscle creatine kinase (MCK) promoter to express Cre...
Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) is a multifunctional Ser/Thr with large interactome. Improved mechanistic understanding of how various CaMKII‐associated proteins (CaMKAPs) interact CaMKII can provide invaluable insight into their biological roles. Previous work by our lab and others has examined the functional relevance single protein‐protein interactions CaMKII, but interactome made physiological consequences specific difficult to study. To address this problem, we...
ABSTRACT The molecular mechanisms that couple plasma membrane receptors/channels to specific intracellular responses, such as increased gene expression, are incompletely understood. postsynaptic scaffolding protein Shank3 associates with Ca 2+ permeable receptors or ion channels can activate many downstream signaling proteins, including calcium/calmodulin-dependent kinase II (CaMKII). Here, we show Shank3/CaMKIIα complexes be specifically co-immunoprecipitated from mouse forebrain lysates,...
Abstract Clustering of neuronal L-type voltage-gated Ca 2+ channels (LTCC) in the plasma membrane is increasingly implicated creating highly localized signaling nanodomains. For example, LTCC activation can increase phosphorylation nuclear CREB transcription factor by increasing concentrations within a nanodomain close to channel, without requiring bulk increases cytosol or nucleus. However, molecular basis for clustering poorly understood. The postsynaptic scaffolding protein Shank3...