A5071760145- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Cardiac electrophysiology and arrhythmias
- Cellular transport and secretion
- Cholinesterase and Neurodegenerative Diseases
- Alzheimer's disease research and treatments
- Protein Kinase Regulation and GTPase Signaling
- Receptor Mechanisms and Signaling
- Mitochondrial Function and Pathology
- Trace Elements in Health
- Calcium signaling and nucleotide metabolism
- ATP Synthase and ATPases Research
- Ion Transport and Channel Regulation
- Ion Channels and Receptors
- Pancreatic function and diabetes
- Genetics and Neurodevelopmental Disorders
- Erythrocyte Function and Pathophysiology
- Electrochemical Analysis and Applications
- Lipid Membrane Structure and Behavior
- Cell death mechanisms and regulation
- NMR spectroscopy and applications
- Analytical Chemistry and Sensors
- Cystic Fibrosis Research Advances
- Endoplasmic Reticulum Stress and Disease
- Mass Spectrometry Techniques and Applications
University of Pennsylvania
2010-2020
Zero to Three
2014
Society for Neuroscience
2014
Czech Academy of Sciences, Institute of Physiology
2007
American Red Cross
2005
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent protein kinase- and ATP-regulated chloride channel, the activity of which determines rate electrolyte fluid transport in variety epithelial tissues. Here we describe mechanism that regulates CFTR channel activity, mediated by PDZ domains, family conserved protein-interaction modules. Na + /H exchanger regulatory factor (NHERF) binds to cytoplasmic tail through either its two (PDZ1 PDZ2) domains. A recombinant...
By altering IP 3 receptor gating, presenilin mutations associated with familial Alzheimer’s disease increase Ca 2+ release from the endoplasmic reticulum.
The Rh blood group proteins are well known as the erythrocyte targets of potent antibody response that causes hemolytic disease newborn. These have been described in molecular detail; however, little is about their function. A transport function suggested by predicted structure and from phylogenetic analysis. To obtain evidence for a role solute transport, we expressed Xenopusoocytes now demonstrate erythroid Rh-associated glycoprotein mediates uptake ammonium across cell membranes....
The mitochondrial uniporter (MCU) is an ion channel that mediates Ca2+ uptake into the matrix to regulate metabolism, cell death, and cytoplasmic signaling. Matrix concentration similar in cytoplasm, despite enormous driving force for entry, but mechanisms prevent overload are unclear. Here, we show MCU activity governed by through EMRE. Deletion or charge neutralization of its matrix-localized acidic C terminus abolishes inhibition currents, resulting activation, enhanced uptake,...
Exaggerated intracellular Ca 2+ signaling is a robust proximal phenotype observed in cells expressing familial Alzheimer's disease (FAD)-causing mutant presenilins (PSs). The mechanisms that underlie this are controversial and their vivo relevance for AD pathogenesis unknown. Here, we used genetic approach to identify the involved evaluate role etiology of two FAD mouse models. Genetic reduction type 1 inositol trisphosphate receptor (InsP 3 R1) by 50% normalized exaggerated cortical...
Single-channel properties of the Xenopus inositol trisphosphate receptor (IP3R) ion channel were examined by patch clamp electrophysiology outer nuclear membrane isolated oocyte nuclei. With 140 mM K+ as charge carrier (cytoplasmic [IP3] = 10 μM, free [Ca2+] 200 nM), IP3R exhibited four and possibly five conductance states. The most-frequently observed state M was 113 pS around 0 mV ∼300 at 60 mV. frequently with high open probability (mean Po 0.4 20 mV). Dwell time distribution analysis...
Familial Alzheimer disease (FAD) is linked to mutations in the presenilin (PS) homologs. FAD mutant PS expression has several cellular consequences, including exaggerated intracellular Ca2+ ([Ca2+]i) signaling due enhanced agonist sensitivity and increased magnitude of [Ca2+]i signals. The mechanisms underlying these phenomena remain controversial. It been proposed that PSs are constitutively active, passive endoplasmic reticulum (ER) leak channels disrupt this function resulting ER store...
The inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) is an endoplasmic reticulum–localized Ca2+-release channel that controls complex cytoplasmic Ca2+ signaling in many cell types. At least three InsP3Rs encoded by different genes have been identified mammalian cells, with primary sequences, subcellular locations, variable ratios of expression, and heteromultimer formation. To examine regulation gating the type 3 isoform, recombinant rat InsP3R (r-InsP3R-3) was expressed Xenopus...
The erythrocyte Rh-associated glycoprotein (RhAG) was recently found to mediate transport of ammonia/ammonium when expressed in Xenopus laevis oocytes and yeast Saccharomyces cerevisiae. Nonerythroid homologs, RhBG RhCG, are the mammalian kidney connecting segment collecting duct, major sites urinary ammonia secretion. This study characterizes properties murine RhCG by ammonium analog [ 14 C]methylamine (MA) uptake two-electrode voltage clamping X. oocytes. Both mediated ammonia, but...
The metabolic sensor AMP-activated protein kinase (AMPK) has emerged as an important link between cellular status and ion transport activity. We previously found that AMPK binds to phosphorylates CFTR in vitro inhibits PKA-dependent stimulation of channel gating Calu-3 bronchial serous gland epithelial cells. To further characterize the mechanism AMPK-dependent regulation CFTR, whole cell patch-clamp measurements were performed with PKA activation cells expressing either constitutively...
Inositol 1,4,5-trisphosphate (InsP3) mobilizes intracellular Ca2+ by binding to its receptor (InsP3R), an endoplasmic reticulum-localized release channel. Patch clamp electrophysiology of Xenopus oocyte nuclei was used study the effects cytoplasmic ATP concentration on ([Ca2+]i) dependence single type 1 InsP3R channels in native reticulum membrane. Cytoplasmic free-acid ([ATP]i), but not MgATP complex, activated gating InsP3-liganded InsP3R, stabilizing open channel state(s) and...
The inositol 1,4,5-trisphosphate receptor (InsP(3)R) is an intracellular Ca(2+)-release channel localized in endoplasmic reticulum (ER) with a central role complex Ca(2+) signaling most cell types. A family of InsP(3)Rs encoded by several genes has been identified different primary sequences, subcellular locations, variable ratios expression, and heteromultimer formation. This diversity suggests that cells require distinct InsP(3)Rs, but the functional correlates this are largely unknown....
The inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) plays a critical role in generation of complex Ca2+ signals many cell types. In patch clamp recordings isolated nuclei from insect Sf9 cells, InsP3R channels were consistently detected with regulation by cytoplasmic InsP3 and free concentrations ([Ca2+]i) very similar to that observed for vertebrate InsP3R. Long channel activity durations the Sf9-InsP3R have now enabled identification novel aspect gating: modal gating. Using...
Modulation of cytoplasmic free Ca2+ concentration ([Ca2+]i) by receptor-mediated generation inositol 1,4,5-trisphosphate (InsP3) and activation its receptor (InsP3R), a Ca2+-release channel in the endoplasmic reticulum, is ubiquitous signalling mechanism. A fundamental aspect InsP3-mediated graded release response to incremental levels stimuli. has transient fast phase, whose rate proportional [InsP3], followed much slower one even constant [InsP3]. Many schemes have been proposed account...
The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) channel is crucial for the generation and modulation of intracellular Ca2+ signals in animal cells. To gain insight into complicated ligand regulation this ubiquitous channel, we constructed a simple quantitative continuous-time Markov-chain model from data. Our accounts most experimentally observed gating behaviors single native IP3R channels insect Sf9 Ligand (Ca2+ IP3) dependencies activity established six main ligand-bound complexes,...
Familial Alzheimer's disease (FAD)-causing mutant presenilins (PS) interact with inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) Ca(2+) release channels resulting in enhanced IP3R channel gating an amyloid beta (Aβ) production-independent manner. This gain-of-function enhancement of activity is considered to be the main reason behind upregulation intracellular signaling presence optimal and suboptimal stimuli spontaneous signals observed cells expressing PS. In this paper, we employed...
The InsP3R Ca2+ release channel has a biphasic dependence on cytoplasmic free concentration ([Ca2+]i). InsP3 activates gating primarily by reducing the sensitivity of to inhibition high [Ca2+]i. To determine if relieving is sufficient for activation, we examined single-channel activities in low [Ca2+]i absence InsP3, patch clamping isolated Xenopus oocyte nuclei. For both endogenous type 1 and recombinant rat 3 channels, spontaneous InsP3-independent with open probability Po (∼0.03) were...
The TRE17 (USP6/TRE-2) oncogene induces tumorigenesis in both humans and mice. However, little is known regarding its regulation or mechanism of transformation. encodes a TBC (Tre-2/Bub2/Cdc16)/Rab GTPase-activating protein homology domain at N terminus ubiquitin-specific protease C terminus. In the current study, we identified ubiquitous calcium (Ca2+)-binding calmodulin (CaM) as novel binding partner for TRE17. CaM bound directly to Ca2+-dependent manner vitro vivo. CaM-binding site was...