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Dive into the research topics where Elizabeth C. King is active.

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Featured researches published by Elizabeth C. King.


Nature Medicine | 2009

Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis

Torsten K. Roepke; Elizabeth C. King; Andrea Reyna-Neyra; Monika Paroder; Kerry Purtell; Wade Koba; Eugene J. Fine; Daniel J. Lerner; Nancy Carrasco; Geoffrey W. Abbott

Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone–stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T4) content and halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T3) and T4 administration to pups, by supplementing dams with T4 before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams; conversely, these symptoms were elicited in Kcne2+/+ pups by feeding exclusively from Kcne2−/− dams. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.


Nature Communications | 2015

FAAH genetic variation enhances fronto-amygdala function in mouse and human

Iva Dincheva; Andrew T. Drysdale; Catherine A. Hartley; David C. Johnson; Deqiang Jing; Elizabeth C. King; Stephen Ra; J. Megan Gray; Ruirong Yang; Ann Marie DeGruccio; Chienchun Huang; Benjamin F. Cravatt; Charles E. Glatt; Matthew N. Hill; B.J. Casey; Francis S. Lee

Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry, and behavior. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviors. These results suggest a gain-of-function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.


PLOS ONE | 2010

Targeted Deletion of Kcne2 Causes Gastritis Cystica Profunda and Gastric Neoplasia

Torsten K. Roepke; Kerry Purtell; Elizabeth C. King; Krista La Perle; Daniel J. Lerner; Geoffrey W. Abbott

Gastric cancer is the second leading cause of cancer death worldwide. Predisposing factors include achlorhydria, Helicobacter pylori infection, oxyntic atrophy and TFF2-expressing metaplasia. In parietal cells, apical potassium channels comprising the KCNQ1 α subunit and the KCNE2 β subunit provide a K+ efflux current to facilitate gastric acid secretion by the apical H+K+ATPase. Accordingly, genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion. Other evidence has suggested a role for KCNE2 in human gastric cancer cell proliferation, independent of its role in gastric acidification. Here, we demonstrate that 1-year-old Kcne2 −/− mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda, 6-fold increased stomach mass, increased Ki67 and nuclear Cyclin D1 expression, and TFF2- and cytokeratin 7-expressing metaplasia. Some Kcne2 −/−mice also exhibited pyloric polypoid adenomas extending into the duodenum, and neoplastic invasion of thin walled vessels in the sub-mucosa. Finally, analysis of human gastric cancer tissue indicated reduced parietal cell KCNE2 expression. Together with previous findings, the results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia.


The FASEB Journal | 2011

KCNE2 forms potassium channels with KCNA3 and KCNQ1 in the choroid plexus epithelium

Torsten K. Roepke; Vikram A. Kanda; Kerry Purtell; Elizabeth C. King; Daniel J. Lerner; Geoffrey W. Abbott

Cerebrospinal fluid (CSF) is crucial for normal function and mechanical protection of the CNS. The choroid plexus epithelium (CPe) is primarily responsible for secreting CSF and regulating its composition by mechanisms currently not fully understood. Previously, the heteromeric KCNQ1‐KCNE2 K+ channel was functionally linked to epithelial processes including gastric acid secretion and thyroid hormone biosynthesis. Here, using Kcne2–/– tissue as a negative control, we found cerebral expression of KCNE2 to be markedly enriched in the CPe apical membrane, where we also discovered expression of KCNQ1. Targeted Kcne2 gene deletion in C57B6 mice increased CPe outward K+ current 2‐fold. The Kcne2 deletion‐enhanced portion of the current was inhibited by XE991 (10 μM) and margatoxin (10 μM) but not by dendrotoxin (100 nM), indicating that it arose from augmentation of KCNQ subfamily and KCNA3 but not KCNA1 K+ channel activity. Kcne2 deletion in C57B6 mice also altered the polarity of CPe KCNQ1 and KCNA3 trafficking, hyperpolarized the CPe membrane by 9 ± 2 mV, and increased CSF [Cl–] by 14% compared with wild‐type mice. These findings constitute the first report of CPe dysfunction caused by cation channel gene disruption and suggest that KCNE2 influences blood‐CSF anion flux by regulating KCNQ1 and KCNA3 in the CPe.—Roepke, T. K., Kanda, V. A., Purtell, K., King, E. C., Lerner, D. J., Abbott, G. W. KCNE2 forms potassium channels with KCNA3 and KCNQ1 in the choroid plexus epithelium. FASEB J. 25, 4264–4273 (2011). www.fasebj.org


Circulation-cardiovascular Genetics | 2014

Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death.

Zhaoyang Hu; Ritu Kant; Marie Anand; Elizabeth C. King; Trine Krogh-Madsen; David J. Christini; Geoffrey W. Abbott

Background—Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in patients with diabetes mellitus. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia-susceptibility genes, including the KCNE2 K+ channel &bgr; subunit, are expressed in multiple tissues, suggesting potential multiplex SCD substrates. Methods and Results—Using whole-transcript transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2–/– mouse pups and adrenal remodeling consistent with metabolic syndrome in adult Kcne2–/– mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes mellitus, hypercholesterolemia, hyperkalemia, anemia, and elevated angiotensin II. Kcne2 deletion was also a prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately after transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia, and AV block. Conclusions—Disruption of a single, widely expressed arrhythmia-susceptibility gene can generate a multisystem syndrome comprising manifold electric and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia-susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.


The FASEB Journal | 2011

Genetic dissection reveals unexpected influence of beta subunits on KCNQ1 K+ channel polarized trafficking in vivo

Torsten K. Roepke; Elizabeth C. King; Kerry Purtell; Vikram A. Kanda; Daniel J. Lerner; Geoffrey W. Abbott

Targeted deletion of the Kcne2 potassium channel β subunit gene ablates gastric acid secretion and predisposes to gastric neoplasia in mice. Here, we discovered that Kcne2 deletion basolaterally reroutes the Kcnq1 α subunit in vivo in parietal cells (PCs), in which the normally apical location of the Kcnq1‐Kcne2 channel facilitates its essential role in gastric acid secretion. Quantitative RT‐PCR and Western blotting revealed that Kcne2 deletion remodeled fundic Kcne3 (2.9±0.8‐fold mRNA increase, n=10;5.3± 0.4‐fold protein increase, n=7) but not Kcne1, 4, or 5, and resulted in basolateral Kcnq1‐Kcne3 complex formation in Kcne2−/− PCs. Concomitant targeted deletion of Kcne3 (creating Kcne2−/−Kcne3−/− mice) restored PC apical Kcnq1 localization without Kcnel, 4, or 5 remodeling (assessed by quantitative RT‐PCR;n=5–10), indicating Kcne3 actively, basolaterally rerouted Kcnq1 in Kcne2−/− PCs. Despite this, Kcne3 deletion exacerbated gastric hyperplasia in Kcne2−/− mice, and both hypochlo‐rhydria and hyperplasia in Kcne2+/− mice, suggesting that Kcne3 up‐regulation was beneficial in Kcne2‐depleted PCs. The findings reveal, in vivo, Kcne‐dependent α subunit polarized trafficking and the existence and consequences of potassium channel β subunit remodeling.—Roepke, T. K., King, E. C., Purtell, K., Kanda, V. A., Lerner, D. J., Abbott, G. W. Genetic dissection reveals unexpected influence of β subunits on KCNQ1 K+ channel polarized trafficking in vivo. FASEB J. 25, 727–736 (2011). www.fasebj.org


PLOS ONE | 2012

Targeted deletion of Kcne2 impairs HCN channel function in mouse thalamocortical circuits.

Shui-Wang Ying; Vikram A. Kanda; Zhaoyang Hu; Kerry Purtell; Elizabeth C. King; Geoffrey W. Abbott; Peter A. Goldstein

Background Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate the pacemaking current, Ih, which regulates neuronal excitability, burst firing activity, rhythmogenesis, and synaptic integration. The physiological consequence of HCN activation depends on regulation of channel gating by endogenous modulators and stabilization of the channel complex formed by principal and ancillary subunits. KCNE2 is a voltage-gated potassium channel ancillary subunit that also regulates heterologously expressed HCN channels; whether KCNE2 regulates neuronal HCN channel function is unknown. Methodology/Principal Findings We investigated the effects of Kcne2 gene deletion on Ih properties and excitability in ventrobasal (VB) and cortical layer 6 pyramidal neurons using brain slices prepared from Kcne2 +/+ and Kcne2 −/− mice. Kcne2 deletion shifted the voltage-dependence of Ih activation to more hyperpolarized potentials, slowed gating kinetics, and decreased Ih density. Kcne2 deletion was associated with a reduction in whole-brain expression of both HCN1 and HCN2 (but not HCN4), although co-immunoprecipitation from whole-brain lysates failed to detect interaction of KCNE2 with HCN1 or 2. Kcne2 deletion also increased input resistance and temporal summation of subthreshold voltage responses; this increased intrinsic excitability enhanced burst firing in response to 4-aminopyridine. Burst duration increased in corticothalamic, but not thalamocortical, neurons, suggesting enhanced cortical excitatory input to the thalamus; such augmented excitability did not result from changes in glutamate release machinery since miniature EPSC frequency was unaltered in Kcne2 −/− neurons. Conclusions/Significance Loss of KCNE2 leads to downregulation of HCN channel function associated with increased excitability in neurons in the cortico-thalamo-cortical loop. Such findings further our understanding of the normal physiology of brain circuitry critically involved in cognition and have implications for our understanding of various disorders of consciousness.


Stress | 2014

Sensitive periods in fear learning and memory.

Elizabeth C. King; Siobhan S. Pattwell; Charles E. Glatt; Francis S. Lee

Abstract Adolescence represents a uniquely sensitive developmental stage in the transition from childhood to adulthood. During this transition, neuronal circuits are particularly susceptible to modification by experience. In addition, adolescence is a stage in which the incidence of anxiety disorders peaks in humans and over 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents. While postnatal critical periods of plasticity for primary sensory processes, such as in the visual system are well established, less is known about potential critical or sensitive periods for fear learning and memory. Here, we review the non-linear developmental aspects of fear learning and memory during a transition period into and out of adolescence. We also review the literature on the non-linear development of GABAergic neurotransmission, a key regulator of critical period plasticity. We provide a model that may inform improved treatment strategies for children and adolescents with fear-related disorders.


Annals of the New York Academy of Sciences | 2013

Nonlinear developmental trajectory of fear learning and memory

Elizabeth C. King; Siobhan S. Pattwell; Alice Sun; Charles E. Glatt; Francis S. Lee

The transition into and out of adolescence is a unique developmental period during which neuronal circuits are particularly susceptible to modification by experience. Adolescence is associated with an increased incidence of anxiety disorders in humans, and an estimated 75% of adults with fear‐related disorders met diagnostic criteria as children and adolescents. Conserved neural circuitry of rodents and humans has facilitated neurodevelopmental studies of behavioral and molecular processes associated with fear learning and memory that lie at the heart of many anxiety disorders. Here, we review the nonlinear developmental aspects of fear learning and memory during a transition period into and out of adolescence and provide a discussion of the molecular mechanisms that may underlie these alterations in behavior. We provide a model that may help to inform novel treatment strategies for children and adolescents with fear‐related disorders.


The FASEB Journal | 2017

Targeted deletion of Kcne3 impairs skeletal muscle function in mice

Elizabeth C. King; Vishal Patel; Marie Anand; Xiaoli Zhao; Shawn M. Crump; Zhaoyang Hu; Noah Weisleder; Geoffrey W. Abbott

KCNE3 (MiRP2) forms heteromeric voltage‐gated K+ channels with the skeletal muscle‐expressed KCNC4 (Kv3.4) a subunit. KCNE3 was the first reported skeletal muscle K+ channel disease gene, but the requirement for KCNE3 in skeletal muscle has been questioned. Here, we confirmed KCNE3 transcript and protein expression in mouse skeletal muscle using Kcne3‐/‐ tissue as a negative control. Whole‐transcript microarray analysis (770,317 probes, interrogating 28,853 transcripts) findings were consistent with Kcne3 deletion increasing gastrocnemius oxidative metabolic gene expression and the proportion of type IIa fast‐twitch oxidative muscle fibers, which was verified using immunofluorescence. The down‐regulated transcript set overlapped with muscle unloading gene expression profiles (‡1.5‐fold change; P < 0.05). Gastrocnemius K+ channel a subunit remodeling arising from Kcne3 deletion was highly specific, involving just 3 of 69 a subunit genes probed: known KCNE3 partners KCNC4 and KCNH2 (mERG) were down‐regulated, and KCNK4 (TRAAK) was up‐regulated (P < 0.05). Functionally, Kcne3‐/‐ mice exhibited abnormal hind‐limb clasping upon tail suspension (63% of Kcne3‐/‐ mice ‡10‐mo‐old vs. 0% age‐matched Kcne3+/+ littermates). Whereas 5 of 5 Kcne3+/+ mice exhibited the typical biphasic decline in contractile force with repetitive stimuli of hind‐limb muscle, both in vivo and in vitro, this was absent in 6 of 6 Kcne3‐/‐ mice tested. Finally, myoblasts isolated from Kcne3‐/‐ mice exhibit faster‐inactivating and smaller sustained outward currents than those from Kcne3+/+ mice. Thus, Kcne3 deletion impairs skeletal muscle function in mice.—King, E. C., Patel, V., Anand, M., Zhao, X., Crump, S. M., Hu, Z., Weisleder, N., Abbott, G. W. Targeted deletion of Kcne3 impairs skeletal muscle function in mice. FASEB J. 31, 2937–2947 (2017). www.fasebj.org

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Zhaoyang Hu

University of California

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Marie Anand

University of California

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