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Geoffrey Stuart Pitt

Adjunct Professor in the Department of Medicine
Medicine, Cardiology
Duke Box 103030, Durham, NC 27710
515 E. 79th Street, Pha, New York, NY 10075

Selected Publications


Mutations of Splicing Regulator RBM20 in Atrial Fibrillation

Journal Article JACC: Basic to Translational Science · February 1, 2024 Full text Cite

A membrane-associated phosphoswitch in Rad controls adrenergic regulation of cardiac calcium channels.

Journal Article J Clin Invest · January 16, 2024 The ability to fight or flee from a threat relies on an acute adrenergic surge that augments cardiac output, which is dependent on increased cardiac contractility and heart rate. This cardiac response depends on β-adrenergic-initiated reversal of the small ... Full text Link to item Cite

Increased Ca2+ signaling through CaV 1.2 induces tendon hypertrophy with increased collagen fibrillogenesis and biomechanical properties.

Journal Article FASEB J · July 2023 Tendons are tension-bearing tissues transmitting force from muscle to bone for body movement. This mechanical loading is essential for tendon development, homeostasis, and healing after injury. While Ca2+ signaling has been studied extensively for its role ... Full text Link to item Cite

Tumour extracellular vesicles and particles induce liver metabolic dysfunction.

Journal Article Nature · June 2023 Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic me ... Full text Link to item Cite

A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes.

Journal Article Nat Cell Biol · April 2023 The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expressio ... Full text Link to item Cite

Rad regulation of CaV1.2 channels controls cardiac fight-or-flight response

Journal Article Nature Cardiovascular Research · November 1, 2022 Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover the primary mechanism underlying the heart’s innate contractile reserve. We show that four protein kinase A (PKA)-phospho ... Full text Cite

Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels.

Journal Article J Neurosci · July 13, 2022 Brain enriched voltage-gated sodium channel (VGSC) Nav1.2 and Nav1.6 are critical for electrical signaling in the CNS. Previous studies have extensively characterized cell-type-specific expression and electrophysiological properties of these two VGSCs and ... Full text Link to item Cite

A dual SHOX2:GFP; MYH6:mCherry knockin hESC reporter line for derivation of human SAN-like cells

Journal Article iScience · April 15, 2022 The sinoatrial node (SAN) is the primary pacemaker of the heart. The human SAN is poorly understood due to limited primary tissue access and limitations in robust in vitro derivation methods. We developed a dual SHOX2:GFP; MYH6:mCherry knockin human embryo ... Full text Cite

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells.

Journal Article Circ Res · April 2022 BACKGROUND: Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysi ... Full text Link to item Cite

Increased Ca2+ influx through CaV1.2 drives aortic valve calcification.

Journal Article JCI Insight · March 8, 2022 Calcific aortic valve disease (CAVD) is heritable, as revealed by recent GWAS. While polymorphisms linked to increased expression of CACNA1C - encoding the CaV1.2 L-type voltage-gated Ca2+ channel - and increased Ca2+ signaling are associated with CAVD, wh ... Full text Link to item Cite

Detecting Cardiovascular Protein-Protein Interactions by Proximity Proteomics.

Journal Article Circ Res · January 21, 2022 Rapidly changing and transient protein-protein interactions regulate dynamic cellular processes in the cardiovascular system. Traditional methods, including affinity purification and mass spectrometry, have revealed many macromolecular complexes in cardiom ... Full text Link to item Cite

Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors.

Journal Article JCI Insight · August 9, 2021 SCN2A, encoding the neuronal voltage-gated Na+ channel NaV1.2, is one of the most commonly affected loci linked to autism spectrum disorders (ASDs). Most ASD-associated mutations in SCN2A are loss-of-function mutations, but studies examining how such mutat ... Full text Link to item Cite

Voltage-Gated Calcium Channels in Nonexcitable Tissues.

Book · February 10, 2021 The identification of a gain-of-function mutation in CACNA1C as the cause of Timothy syndrome, a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted roles for the L-type voltage-gated Ca2+ channel CaV1.2 in nonexcitable cells. Pr ... Full text Link to item Cite

A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain.

Journal Article Nat Commun · January 19, 2021 Splicing varies across brain regions, but the single-cell resolution of regional variation is unclear. We present a single-cell investigation of differential isoform expression (DIE) between brain regions using single-cell long-read sequencing in mouse hip ... Full text Link to item Cite

Adrenergic CaV1.2 Activation via Rad Phosphorylation Converges at α1C I-II Loop.

Journal Article Circ Res · January 8, 2021 RATIONALE: Changing activity of cardiac CaV1.2 channels under basal conditions, during sympathetic activation, and in heart failure is a major determinant of cardiac physiology and pathophysiology. Although cardiac CaV1.2 channels are prominently upregulat ... Full text Link to item Cite

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Nav1.5.

Journal Article Channels (Austin) · December 2020 The cardiac voltage-gated sodium channel Nav1.5 conducts the rapid inward sodium current crucial for cardiomyocyte excitability. Loss-of-function mutations in its gene SCN5A are linked to cardiac arrhythmias such as Brugada Syndrome (BrS). Several BrS-asso ... Full text Link to item Cite

Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

Journal Article Neurology · November 24, 2020 OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebel ... Full text Open Access Link to item Cite

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels.

Journal Article JCI Insight · October 2, 2020 The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the NaV1.5 interactome in regulating late Na+ current in ca ... Full text Link to item Cite

An interaction between the III-IV linker and CTD in NaV1.5 confers regulation of inactivation by CaM and FHF.

Journal Article J Gen Physiol · February 3, 2020 Voltage gated sodium channel (VGSC) activation drives the action potential upstroke in cardiac myocytes, skeletal muscles, and neurons. After opening, VGSCs rapidly enter a non-conducting, inactivated state. Impaired inactivation causes persistent inward c ... Full text Link to item Cite

Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics.

Journal Article Nature · January 2020 Increased cardiac contractility during the fight-or-flight response is caused by β-adrenergic augmentation of CaV1.2 voltage-gated calcium channels1-4. However, this augmentation persists in transgenic murine hearts expressing mutant CaV1.2 α1C and β subun ... Full text Link to item Cite

Mutations of Splicing Regulator RBM20 in Atrial Fibrillation

Journal Article JACC: Basic to Translational Science · February 1, 2024 Full text Cite

A membrane-associated phosphoswitch in Rad controls adrenergic regulation of cardiac calcium channels.

Journal Article J Clin Invest · January 16, 2024 The ability to fight or flee from a threat relies on an acute adrenergic surge that augments cardiac output, which is dependent on increased cardiac contractility and heart rate. This cardiac response depends on β-adrenergic-initiated reversal of the small ... Full text Link to item Cite

Increased Ca2+ signaling through CaV 1.2 induces tendon hypertrophy with increased collagen fibrillogenesis and biomechanical properties.

Journal Article FASEB J · July 2023 Tendons are tension-bearing tissues transmitting force from muscle to bone for body movement. This mechanical loading is essential for tendon development, homeostasis, and healing after injury. While Ca2+ signaling has been studied extensively for its role ... Full text Link to item Cite

Tumour extracellular vesicles and particles induce liver metabolic dysfunction.

Journal Article Nature · June 2023 Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic me ... Full text Link to item Cite

A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes.

Journal Article Nat Cell Biol · April 2023 The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expressio ... Full text Link to item Cite

Rad regulation of CaV1.2 channels controls cardiac fight-or-flight response

Journal Article Nature Cardiovascular Research · November 1, 2022 Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover the primary mechanism underlying the heart’s innate contractile reserve. We show that four protein kinase A (PKA)-phospho ... Full text Cite

Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels.

Journal Article J Neurosci · July 13, 2022 Brain enriched voltage-gated sodium channel (VGSC) Nav1.2 and Nav1.6 are critical for electrical signaling in the CNS. Previous studies have extensively characterized cell-type-specific expression and electrophysiological properties of these two VGSCs and ... Full text Link to item Cite

A dual SHOX2:GFP; MYH6:mCherry knockin hESC reporter line for derivation of human SAN-like cells

Journal Article iScience · April 15, 2022 The sinoatrial node (SAN) is the primary pacemaker of the heart. The human SAN is poorly understood due to limited primary tissue access and limitations in robust in vitro derivation methods. We developed a dual SHOX2:GFP; MYH6:mCherry knockin human embryo ... Full text Cite

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells.

Journal Article Circ Res · April 2022 BACKGROUND: Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysi ... Full text Link to item Cite

Increased Ca2+ influx through CaV1.2 drives aortic valve calcification.

Journal Article JCI Insight · March 8, 2022 Calcific aortic valve disease (CAVD) is heritable, as revealed by recent GWAS. While polymorphisms linked to increased expression of CACNA1C - encoding the CaV1.2 L-type voltage-gated Ca2+ channel - and increased Ca2+ signaling are associated with CAVD, wh ... Full text Link to item Cite

Detecting Cardiovascular Protein-Protein Interactions by Proximity Proteomics.

Journal Article Circ Res · January 21, 2022 Rapidly changing and transient protein-protein interactions regulate dynamic cellular processes in the cardiovascular system. Traditional methods, including affinity purification and mass spectrometry, have revealed many macromolecular complexes in cardiom ... Full text Link to item Cite

Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors.

Journal Article JCI Insight · August 9, 2021 SCN2A, encoding the neuronal voltage-gated Na+ channel NaV1.2, is one of the most commonly affected loci linked to autism spectrum disorders (ASDs). Most ASD-associated mutations in SCN2A are loss-of-function mutations, but studies examining how such mutat ... Full text Link to item Cite

Voltage-Gated Calcium Channels in Nonexcitable Tissues.

Book · February 10, 2021 The identification of a gain-of-function mutation in CACNA1C as the cause of Timothy syndrome, a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted roles for the L-type voltage-gated Ca2+ channel CaV1.2 in nonexcitable cells. Pr ... Full text Link to item Cite

A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain.

Journal Article Nat Commun · January 19, 2021 Splicing varies across brain regions, but the single-cell resolution of regional variation is unclear. We present a single-cell investigation of differential isoform expression (DIE) between brain regions using single-cell long-read sequencing in mouse hip ... Full text Link to item Cite

Adrenergic CaV1.2 Activation via Rad Phosphorylation Converges at α1C I-II Loop.

Journal Article Circ Res · January 8, 2021 RATIONALE: Changing activity of cardiac CaV1.2 channels under basal conditions, during sympathetic activation, and in heart failure is a major determinant of cardiac physiology and pathophysiology. Although cardiac CaV1.2 channels are prominently upregulat ... Full text Link to item Cite

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Nav1.5.

Journal Article Channels (Austin) · December 2020 The cardiac voltage-gated sodium channel Nav1.5 conducts the rapid inward sodium current crucial for cardiomyocyte excitability. Loss-of-function mutations in its gene SCN5A are linked to cardiac arrhythmias such as Brugada Syndrome (BrS). Several BrS-asso ... Full text Link to item Cite

Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

Journal Article Neurology · November 24, 2020 OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebel ... Full text Open Access Link to item Cite

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels.

Journal Article JCI Insight · October 2, 2020 The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the NaV1.5 interactome in regulating late Na+ current in ca ... Full text Link to item Cite

An interaction between the III-IV linker and CTD in NaV1.5 confers regulation of inactivation by CaM and FHF.

Journal Article J Gen Physiol · February 3, 2020 Voltage gated sodium channel (VGSC) activation drives the action potential upstroke in cardiac myocytes, skeletal muscles, and neurons. After opening, VGSCs rapidly enter a non-conducting, inactivated state. Impaired inactivation causes persistent inward c ... Full text Link to item Cite

Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics.

Journal Article Nature · January 2020 Increased cardiac contractility during the fight-or-flight response is caused by β-adrenergic augmentation of CaV1.2 voltage-gated calcium channels1-4. However, this augmentation persists in transgenic murine hearts expressing mutant CaV1.2 α1C and β subun ... Full text Link to item Cite

Ca2+/CaM interaction with voltage-gated Na+ channels.

Journal Article Proc Natl Acad Sci U S A · December 26, 2019 Full text Link to item Cite

Knockout of the X-linked Fgf13 in the hypothalamic paraventricular nucleus impairs sympathetic output to brown fat and causes obesity.

Journal Article FASEB J · October 2019 Fibroblast growth factor (FGF)13, a nonsecreted, X-linked, FGF homologous factor, is differentially expressed in adipocytes in response to diet, yet Fgf13's role in metabolism has not been explored. Heterozygous Fgf13 knockouts fed normal chow and housed a ... Full text Link to item Cite

The CaV1.2 L-type calcium channel regulates bone homeostasis in the middle and inner ear.

Journal Article Bone · August 2019 Bone remodeling of the auditory ossicles and the otic capsule is highly restricted and tightly controlled by the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-Β ligand (RANKL)/receptor activator of nuclear factor kappa-Β (RANK) system. I ... Full text Link to item Cite

Cardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking.

Journal Article J Clin Invest · February 1, 2019 Ca2+ channel β-subunit interactions with pore-forming α-subunits are long-thought to be obligatory for channel trafficking to the cell surface and for tuning of basal biophysical properties in many tissues. Unexpectedly, we demonstrate that transgenic expr ... Full text Link to item Cite

The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction.

Journal Article J Clin Invest · November 1, 2018 Cardiac two-pore domain potassium channels (K2P) exist in organisms from Drosophila to humans; however, their role in cardiac function is not known. We identified a K2P gene, CG8713 (sandman), in a Drosophila genetic screen and show that sandman is critica ... Full text Link to item Cite

Progress in Understanding and Treating SCN2A-Mediated Disorders.

Journal Article Trends Neurosci · July 2018 Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel NaV1.2. Functional assa ... Full text Link to item Cite

Fibroblast Growth Factor Homologous Factors Modulate Cardiac Sodium and Calcium Channels

Chapter · January 1, 2018 Fibroblast growth factor homologous factors (FHFs) are a noncanonical subset of intracellular fibroblast growth factors that do not function as growth factors but have been implicated in a variety of biological processes and in disease. In the heart, they ... Full text Cite

Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss.

Journal Article JCI Insight · November 16, 2017 While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for CaV1.2 L-type voltage-gated Ca2+ channels in osteogenesis and exploit a transgenic gain-of-func ... Full text Link to item Cite

Proteolytic cleavage and PKA phosphorylation of α1C subunit are not required for adrenergic regulation of CaV1.2 in the heart.

Journal Article Proc Natl Acad Sci U S A · August 22, 2017 Calcium influx through the voltage-dependent L-type calcium channel (CaV1.2) rapidly increases in the heart during "fight or flight" through activation of the β-adrenergic and protein kinase A (PKA) signaling pathway. The precise molecular mechanisms of β- ... Full text Link to item Cite

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload.

Journal Article Proc Natl Acad Sci U S A · May 16, 2017 The fibroblast growth factor (FGF) homologous factor FGF13, a noncanonical FGF, has been best characterized as a voltage-gated Na+ channel auxiliary subunit. Other cellular functions have been suggested, but not explored. In inducible, cardiac-specific Fgf ... Full text Link to item Cite

Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles.

Journal Article J Mol Cell Cardiol · March 2017 The intracellular fibroblast growth factors (iFGF/FHFs) bind directly to cardiac voltage gated Na+ channels, and modulate their function. Mutations that affect iFGF/FHF-Na+ channel interaction are associated with arrhythmia syndromes. Although suspected to ... Full text Link to item Cite

Calmodulin limits pathogenic Na+ channel persistent current.

Journal Article J Gen Physiol · February 2017 Increased "persistent" current, caused by delayed inactivation, through voltage-gated Na+ (NaV) channels leads to cardiac arrhythmias or epilepsy. The underlying molecular contributors to these inactivation defects are poorly understood. Here, we show that ... Full text Link to item Cite

A view from the side-line.

Journal Article Eur Heart J · December 14, 2016 Full text Link to item Cite

FGF13 modulates the gating properties of the cardiac sodium channel Nav1.5 in an isoform-specific manner.

Journal Article Channels (Austin) · September 2, 2016 FGF13 (FHF2), the major fibroblast growth factor homologous factor (FHF) in rodent heart, directly binds to the C-terminus of the main cardiac sodium channel, NaV1.5. Knockdown of FGF13 in cardiomyocytes induces slowed ventricular conduction by altering Na ... Full text Link to item Cite

Current view on regulation of voltage-gated sodium channels by calcium and auxiliary proteins.

Journal Article Protein Sci · September 2016 In cardiac and skeletal myocytes, and in most neurons, the opening of voltage-gated Na(+) channels (NaV channels) triggers action potentials, a process that is regulated via the interactions of the channels' intercellular C-termini with auxiliary proteins ... Full text Link to item Cite

Targeted Epigenetic Remodeling of Endogenous Loci by CRISPR/Cas9-Based Transcriptional Activators Directly Converts Fibroblasts to Neuronal Cells.

Journal Article Cell Stem Cell · September 1, 2016 Overexpression of exogenous fate-specifying transcription factors can directly reprogram differentiated somatic cells to target cell types. Here, we show that similar reprogramming can also be achieved through the direct activation of endogenous genes usin ... Full text Link to item Cite

Ion Channels in Health and Disease

Book · July 29, 2016 Ion Channels in Health and Disease provides key insight to allow researchers to generate discoveries across disease states. A single resource that integrates disparate areas of biology and disease ion channel biology, this publication includes cross-refere ... Full text Cite

Preface

Book · July 29, 2016 Full text Cite

Long QT Syndrome and Seizures.

Journal Article JACC Clin Electrophysiol · June 2016 Full text Link to item Cite

Polarized localization of voltage-gated Na+ channels is regulated by concerted FGF13 and FGF14 action.

Journal Article Proc Natl Acad Sci U S A · May 10, 2016 Clustering of voltage-gated sodium channels (VGSCs) within the neuronal axon initial segment (AIS) is critical for efficient action potential initiation. Although initially inserted into both somatodendritic and axonal membranes, VGSCs are concentrated wit ... Full text Link to item Cite

A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias.

Journal Article J Mol Cell Cardiol · March 2016 BACKGROUND: Inherited autosomal dominant mutations in cardiac sodium channels (NaV1.5) cause various arrhythmias, such as long QT syndrome and Brugada syndrome. Although dozens of mutations throughout the protein have been reported, there are few reported ... Full text Link to item Cite

Fibroblast Growth Factor Homologous Factors: New Roles in Neuronal Health and Disease.

Journal Article Neuroscientist · February 2016 Fibroblast growth factor homologous factors (FHFs) are a noncanonical subset of intracellular fibroblast growth factors that have been implicated in a variety of neurobiological processes and in disease. They are most prominently regulators of voltage-gate ... Full text Link to item Cite

α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current.

Journal Article PLoS One · 2016 Drug-induced long-QT syndrome (diLQTS) is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with ... Full text Link to item Cite

STIM1-Ca2+ signaling modulates automaticity of the mouse sinoatrial node.

Conference Proc Natl Acad Sci U S A · October 13, 2015 Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca(2+) release from internal Ca(2+) s ... Full text Link to item Cite

SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia.

Journal Article Proc Natl Acad Sci U S A · October 6, 2015 Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that ... Full text Link to item Cite

Cardiovascular precision medicine: hope or hype?

Journal Article Eur Heart J · August 1, 2015 Full text Link to item Cite

Na+ channel function, regulation, structure, trafficking and sequestration.

Journal Article J Physiol · March 15, 2015 This paper is the second of a series of three reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation-contraction coupling and arrhythmias: Na(+) ... Full text Link to item Cite

Calcium signaling regulates ventricular hypertrophy during development independent of contraction or blood flow.

Journal Article J Mol Cell Cardiol · March 2015 In utero interventions aimed at restoring left ventricular hemodynamic forces in fetuses with prenatally diagnosed hypoplastic left heart syndrome failed to stimulate ventricular myocardial growth during gestation, suggesting chamber growth during developm ... Full text Link to item Cite

The PDZ motif of the α1C subunit is not required for surface trafficking and adrenergic modulation of CaV1.2 channel in the heart.

Journal Article J Biol Chem · January 23, 2015 Voltage-gated Ca(2+) channels play a key role in initiating muscle excitation-contraction coupling, neurotransmitter release, gene expression, and hormone secretion. The association of CaV1.2 with a supramolecular complex impacts trafficking, localization, ... Full text Link to item Cite

Calcium Channel Mutations in Cardiac Arrhythmia Syndromes.

Journal Article Curr Mol Pharmacol · 2015 Voltage gated calcium channels are essential for cardiac physiology by serving as sarcolemma- restricted gatekeepers for calcium in cardiac myocytes. Activation of the L-type voltagegated calcium channel provides the calcium entry required for excitation-c ... Full text Link to item Cite

FGF14 modulates resurgent sodium current in mouse cerebellar Purkinje neurons.

Journal Article Elife · September 30, 2014 Rapid firing of cerebellar Purkinje neurons is facilitated in part by a voltage-gated Na(+) (NaV) 'resurgent' current, which allows renewed Na(+) influx during membrane repolarization. Resurgent current results from unbinding of a blocking particle that co ... Full text Link to item Cite

Structural analyses of Ca²⁺/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation.

Journal Article Nat Commun · September 18, 2014 Ca(2+) regulates voltage-gated Na(+) (NaV) channels, and perturbed Ca(2+) regulation of NaV function is associated with epilepsy syndromes, autism and cardiac arrhythmias. Understanding the disease mechanisms, however, has been hindered by a lack of struct ... Full text Link to item Cite

Ion channels under the sun.

Journal Article FASEB J · May 2014 Full text Link to item Cite

A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis.

Journal Article PLoS One · 2014 Mutations in CACNA1C that increase current through the CaV1.2 L-type Ca2+ channel underlie rare forms of long QT syndrome (LQTS), and Timothy syndrome (TS). We identified a variant in CACNA1C in a male child of Filipino descent with arrhythmias and extraca ... Full text Link to item Cite

FGF12 is a candidate Brugada syndrome locus.

Journal Article Heart Rhythm · December 2013 BACKGROUND: Less than 30% of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recen ... Full text Link to item Cite

FGF12 is a Novel Brugada Syndrome Locus

Conference CIRCULATION · November 26, 2013 Link to item Cite

A CACNA1C Mutation that Causes a Subset of Timothy Syndrome Phenotypes Correlates.

Journal Article Heart Rhythm · November 2013 Timothy syndrome (TS) is a rare congenital long QT syndrome (LQTS) associated with extracardiac manifestations including craniofacial dysmorphia and dental abnormalities. The locus for TS is CACNA1C, which encodes the CaV1.2 L-type Ca(2+) channel, for whic ... Full text Link to item Cite

Fibroblast growth factor homologous factors modulate cardiac calcium channels.

Journal Article Circ Res · August 2, 2013 RATIONALE: Fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-14) are intracellular modulators of voltage-gated Na+ channels, but their cellular distribution in cardiomyocytes indicated that they performed other functions. OBJECTIVE: We aimed t ... Full text Link to item Cite

FGF14 regulates presynaptic Ca2+ channels and synaptic transmission.

Journal Article Cell Rep · July 11, 2013 Featured Publication Fibroblast growth factor homologous factors (FHFs) are not growth factors, but instead bind to voltage-gated Na+ channels (NaV) and regulate their function. Mutations in FGF14, an FHF that is the locus for spinocerebellar ataxia 27 (SCA27), are believed to ... Full text Link to item Cite

The auxiliary subunit KChIP2 is an essential regulator of homeostatic excitability.

Journal Article J Biol Chem · May 10, 2013 BACKGROUND: The necessity for, or redundancy of, distinctive KChIP proteins is not known. RESULTS: Deletion of KChIP2 leads to increased susceptibility to epilepsy and to a reduction in IA and increased excitability in pyramidal hippocampal neurons. CONCLU ... Full text Link to item Cite

Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development.

Journal Article J Clin Invest · April 2013 Featured Publication The identification of a gain-of-function mutation in CACNA1C as the cause of Timothy Syndrome (TS), a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted unexpected roles for the L-type voltage-gated Ca2+ channel CaV1.2 in nonexc ... Full text Link to item Cite

Calmodulin and CaMKII as Ca2+ Switches for Cardiac Ion Channels

Chapter · January 1, 2013 Changes in intracellular Ca2+ are among the most diverse and important means of cell signaling. In the heart, signaling pathways from excitation-contraction coupling to humoral activation of hypertrophic responses all rely on changes in the concentration o ... Full text Cite

Long-term in vivo imaging of multiple organs at the single cell level.

Journal Article PLoS One · 2013 Two-photon microscopy has enabled the study of individual cell behavior in live animals. Many organs and tissues cannot be studied, especially longitudinally, because they are located too deep, behind bony structures or too close to the lung and heart. Her ... Full text Link to item Cite

Can polymorphisms predict response to antiarrhythmic drugs in atrial fibrillation?

Journal Article J Am Coll Cardiol · August 7, 2012 Featured Publication Full text Link to item Cite

A VGF-derived peptide attenuates development of type 2 diabetes via enhancement of islet β-cell survival and function.

Journal Article Cell Metab · July 3, 2012 Featured Publication Deterioration of functional islet β-cell mass is the final step in progression to Type 2 diabetes. We previously reported that overexpression of Nkx6.1 in rat islets has the dual effects of enhancing glucose-stimulated insulin secretion (GSIS) and increasi ... Full text Link to item Cite

Crystal structure of the ternary complex of a NaV C-terminal domain, a fibroblast growth factor homologous factor, and calmodulin.

Journal Article Structure · July 3, 2012 Featured Publication Voltage-gated Na⁺ (Na(V)) channels initiate neuronal action potentials. Na(V) channels are composed of a transmembrane domain responsible for voltage-dependent Na⁺ conduction and a cytosolic C-terminal domain (CTD) that regulates channel function through i ... Full text Link to item Cite

Thermosensory and nonthermosensory isoforms of Drosophila melanogaster TRPA1 reveal heat-sensor domains of a thermoTRP Channel.

Journal Article Cell Rep · January 26, 2012 Featured Publication Specialized somatosensory neurons detect temperatures ranging from pleasantly cool or warm to burning hot and painful (nociceptive). The precise temperature ranges sensed by thermally sensitive neurons is determined by tissue-specific expression of ion cha ... Full text Link to item Cite

Dissection of a quantitative trait locus for PR interval duration identifies Tnni3k as a novel modulator of cardiac conduction.

Journal Article PLoS Genet · 2012 Atrio-ventricular conduction disease is a common feature in Mendelian rhythm disorders associated with sudden cardiac death and is characterized by prolongation of the PR interval on the surface electrocardiogram (ECG). Prolongation of the PR interval is a ... Full text Link to item Cite

Novel Roles of Fibroblast Growth Factor Homologous Factors in Heart

Journal Article Biophysical Journal · January 2012 Full text Cite

Fibroblast growth factor homologous factors in the heart: a potential locus for cardiac arrhythmias.

Journal Article Trends Cardiovasc Med · October 2011 The four fibroblast growth factor homologous factors (FHFs; FGF11-FGF14) are intracellular proteins that bind and modulate voltage-gated sodium channels (VGSCs). Although FHFs have been well studied in neurons and implicated in neurologic disease, their ro ... Full text Link to item Cite

Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts.

Journal Article Circ Res · September 16, 2011 Featured Publication RATIONALE: Fibroblast growth factor homologous factors (FHFs), a subfamily of fibroblast growth factors (FGFs) that are incapable of functioning as growth factors, are intracellular modulators of Na(+) channels and have been linked to neurodegenerative dis ... Full text Link to item Cite

Identification of novel interaction sites that determine specificity between fibroblast growth factor homologous factors and voltage-gated sodium channels.

Journal Article J Biol Chem · July 8, 2011 Featured Publication Fibroblast growth factor homologous factors (FHFs, FGF11-14) bind to the C termini (CTs) of specific voltage-gated sodium channels (VGSC) and thereby regulate their function. The effect of an individual FHF on a specific VGSC varies greatly depending upon ... Full text Link to item Cite

The S1103Y cardiac sodium channel variant is associated with implantable cardioverter-defibrillator events in blacks with heart failure and reduced ejection fraction.

Journal Article Circ Cardiovasc Genet · April 2011 Featured Publication BACKGROUND: Risk-stratifying heart failure patients for primary prevention implantable cardioverter-defibrillators (ICDs) remains a challenge, especially for blacks, who have an increased incidence of sudden cardiac death but have been underrepresented in ... Full text Link to item Cite

Rem2-targeted shRNAs reduce frequency of miniature excitatory postsynaptic currents without altering voltage-gated Ca²⁺ currents.

Journal Article PLoS One · 2011 Ca²⁺ influx through voltage-gated Ca²⁺ channels (VGCCs) plays important roles in neuronal cell development and function. Rem2 is a member of the RGK (Rad, Rem, Rem2, Gem/Kir) subfamily of small GTPases that confers potent inhibition upon VGCCs. The physiol ... Full text Link to item Cite

Rationale and design of the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository.

Journal Article Am Heart J · November 2009 BACKGROUND: Disturbances in cardiac rhythm can lead to significant morbidity and mortality. Many arrhythmias are known to have a heritable component, but the degree to which genetic variation contributes to disease risk and morbidity is poorly understood. ... Full text Link to item Cite

Accessory subunit KChIP2 modulates the cardiac L-type calcium current.

Journal Article Circ Res · June 19, 2009 Featured Publication Complex modulation of voltage-gated Ca2+ currents through the interplay among Ca2+ channels and various Ca(2+)-binding proteins is increasingly being recognized. The K+ channel interacting protein 2 (KChIP2), originally identified as an auxiliary subunit f ... Full text Link to item Cite

Genetics of cardiac repolarization.

Journal Article Nat Genet · April 2009 Featured Publication Prolongation of the electrocardiographic QT interval, a measure of cardiac repolarization, is associated with arrhythmogenic disorders and is a risk factor for sudden cardiac death. Two genome-wide association studies (GWAS) of variation in the QT interval ... Full text Link to item Cite

Solution structure of the NaV1.2 C-terminal EF-hand domain.

Journal Article J Biol Chem · March 6, 2009 Featured Publication Voltage-gated sodium channels initiate the rapid upstroke of action potentials in many excitable tissues. Mutations within intracellular C-terminal sequences of specific channels underlie a diverse set of channelopathies, including cardiac arrhythmias and ... Full text Link to item Cite

Ca2+/CaM controls Ca2+-dependent inactivation of NMDA receptors by dimerizing the NR1 C termini.

Journal Article J Neurosci · February 20, 2008 Featured Publication Ca2+ influx through NMDA receptors (NMDARs) leads to channel inactivation, which limits Ca2+ entry and protects against excitotoxicity. Extensive functional data suggests that this Ca2+-dependent inactivation (CDI) requires both calmodulin (CaM) binding to ... Full text Link to item Cite

Ca2+/calmodulin regulates trafficking of Ca(V)1.2 Ca2+ channels in cultured hippocampal neurons.

Journal Article J Neurosci · August 22, 2007 Featured Publication As the Ca2+-sensor for Ca2+-dependent inactivation, calmodulin (CaM) has been proposed, but never definitively demonstrated, to be a constitutive Ca(V)1.2 Ca2+ channel subunit. Here we show that CaM is associated with the Ca(V)1.2 pore-forming alpha1C subu ... Full text Link to item Cite

Response to Kloner and Cannom

Journal Article Circulation · June 1, 2007 Full text Cite

Calmodulin and CaMKII as molecular switches for cardiac ion channels.

Journal Article Cardiovasc Res · March 1, 2007 Featured Publication Because changes in intracellular Ca(2+) concentration are the final signals of electrical activity in excitable cells, many mechanisms have evolved to regulate Ca(2+) influx. Among the most important are those pathways that directly regulate the ion channe ... Full text Link to item Cite

Dose-dependent and isoform-specific modulation of Ca2+ channels by RGK GTPases.

Journal Article J Gen Physiol · November 2006 Featured Publication Although inhibition of voltage-gated calcium channels by RGK GTPases (RGKs) represents an important mode of regulation to control Ca(2+) influx in excitable cells, their exact mechanism of inhibition remains controversial. This has prevented an understandi ... Full text Link to item Cite

Remodeled cardiac calcium channels.

Journal Article J Mol Cell Cardiol · September 2006 Featured Publication Cardiac calcium channels play a pivotal role in the proper functioning of cardiac cells. In response to various pathologic stimuli, they become remodeled, changing how they function, as they adapt to their new environment. Specific features of remodeled ch ... Full text Link to item Cite

Aldosterone, ion channels, and sudden death: another piece of the circle?

Journal Article Am J Physiol Heart Circ Physiol · June 2006 Featured Publication Full text Link to item Cite

The real estate of cardiac signaling: location, location, location.

Journal Article Proc Natl Acad Sci U S A · May 16, 2006 Featured Publication Full text Link to item Cite

KCNQ1 assembly and function is blocked by long-QT syndrome mutations that disrupt interaction with calmodulin.

Journal Article Circ Res · April 28, 2006 Featured Publication Calmodulin (CaM) has been recognized as an obligate subunit for many ion channels in which its function has not been clearly established. Because channel subunits associate early during channel biosynthesis, CaM may provide a mechanism for Ca(2+)-dependent ... Full text Link to item Cite

CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation.

Journal Article J Cell Biol · November 7, 2005 Featured Publication Ca2+-dependent facilitation (CDF) of voltage-gated calcium current is a powerful mechanism for up-regulation of Ca2+ influx during repeated membrane depolarization. CDF of L-type Ca2+ channels (Ca(v)1.2) contributes to the positive force-frequency effect i ... Full text Link to item Cite

Essential Ca(V)beta modulatory properties are AID-independent.

Journal Article Nat Struct Mol Biol · April 2005 Featured Publication Voltage-gated Ca(2+) channel beta (Ca(v)beta) subunits have a highly conserved core consisting of interacting Src homology 3 and guanylate kinase domains, and are postulated to exert their effects through AID, the major interaction site in the pore-forming ... Full text Link to item Cite

Calmodulin mediates Ca2+ sensitivity of sodium channels.

Journal Article J Biol Chem · October 22, 2004 Featured Publication Ca2+ has been proposed to regulate Na+ channels through the action of calmodulin (CaM) bound to an IQ motif or through direct binding to a paired EF hand motif in the Nav1 C terminus. Mutations within these sites cause cardiac arrhythmias or autism, but de ... Full text Link to item Cite

Calcium channel function regulated by the SH3-GK module in beta subunits.

Journal Article Neuron · April 8, 2004 Featured Publication beta subunits of voltage-gated calcium channels (VGCCs) regulate channel trafficking and function, thereby shaping the intensity and duration of intracellular changes in calcium. beta subunits share limited sequence homology with the Src homology 3-guanyla ... Full text Link to item Cite

Identification of the components controlling inactivation of voltage-gated Ca2+ channels.

Journal Article Neuron · March 4, 2004 Featured Publication Ca(2+)-dependent inactivation (CDI) of L-type voltage-gated Ca(2+) channels limits Ca(2+) entry into neurons, thereby regulating numerous cellular events. Here we present the isolation and purification of the Ca(2+)-sensor complex, consisting of calmodulin ... Full text Link to item Cite

Molecular basis of calmodulin tethering and Ca2+-dependent inactivation of L-type Ca2+ channels.

Journal Article J Biol Chem · August 17, 2001 Ca(2+)-dependent inactivation (CDI) of L-type Ca(2+) channels plays a critical role in controlling Ca(2+) entry and downstream signal transduction in excitable cells. Ca(2+)-insensitive forms of calmodulin (CaM) act as dominant negatives to prevent CDI, su ... Full text Link to item Cite

Ca2+-sensitive inactivation and facilitation of L-type Ca2+ channels both depend on specific amino acid residues in a consensus calmodulin-binding motif in the(alpha)1C subunit.

Journal Article J Biol Chem · July 14, 2000 L-type Ca(2+) channels are unusual in displaying two opposing forms of autoregulatory feedback, Ca(2+)-dependent inactivation and facilitation. Previous studies suggest that both involve direct interactions between calmodulin (CaM) and a consensus CaM-bind ... Full text Link to item Cite

Calmodulin supports both inactivation and facilitation of L-type calcium channels.

Journal Article Nature · May 13, 1999 L-type Ca2+ channels support Ca2+ entry into cells, which triggers cardiac contraction, controls hormone secretion from endocrine cells and initiates transcriptional events that support learning and memory. These channels are examples of molecular signal-t ... Full text Link to item Cite

Role of cAMP-dependent protein kinase in controlling aggregation and postaggregative development in Dictyostelium.

Journal Article Dev Biol · March 15, 1997 We have examined the role of cAMP-dependent protein kinase (PKA) in controlling aggregation and postaggregative development in Dictyostelium. We previously showed that cells in which the gene encoding the PKA catalytic subunit has been disrupted (pkacat- c ... Full text Link to item Cite

Adenylyl cyclase G, an osmosensor controlling germination of Dictyostelium spores.

Journal Article J Biol Chem · September 27, 1996 Dictyostelium cells express a G-protein-coupled adenylyl cyclase, ACA, during aggregation and an atypical adenylyl cyclase, ACG, in mature spores. The ACG gene was disrupted by homologous recombination. acg- cells developed into normal fruiting bodies with ... Full text Link to item Cite

Extracellular cAMP is sufficient to restore developmental gene expression and morphogenesis in Dictyostelium cells lacking the aggregation adenylyl cyclase (ACA).

Journal Article Genes Dev · November 1993 Cell movement and cell-type-specific gene expression during Dictyostelium development are regulated by cAMP, which functions both as an extracellular hormone-like signal and an intracellular second messenger. Previous data indicated that aca- mutants, whic ... Full text Link to item Cite

Multiple cyclic AMP receptors are linked to adenylyl cyclase in Dictyostelium.

Journal Article Mol Biol Cell · November 1992 cAMP receptor 1 and G-protein alpha-subunit 2 null cell lines (car1- and g alpha 2-) were examined to assess the roles that these two proteins play in cAMP stimulated adenylyl cyclase activation in Dictyostelium. In intact wild-type cells, cAMP stimulation ... Full text Link to item Cite

Amino acid substitutions in the Dictyostelium G alpha subunit G alpha 2 produce dominant negative phenotypes and inhibit the activation of adenylyl cyclase, guanylyl cyclase, and phospholipase C.

Journal Article Mol Biol Cell · July 1992 Previous studies have demonstrated that the Dictyostelium G alpha subunit G alpha 2 is essential for the cAMP-activation of adenylyl cyclase and guanylyl cyclase and that g alpha 2 null mutants do not aggregate. In this manuscript, we extend the analysis o ... Full text Link to item Cite

Structurally distinct and stage-specific adenylyl cyclase genes play different roles in Dictyostelium development.

Journal Article Cell · April 17, 1992 We have isolated two adenylyl cyclase genes, designated ACA and ACG, from Dictyostelium. The proposed structure for ACA resembles that proposed for mammalian adenylyl cyclases: two large hydrophilic domains and two sets of six transmembrane spans. ACG has ... Full text Link to item Cite

Mechanisms of excitation and adaptation in Dictyostelium.

Journal Article Semin Cell Biol · April 1990 A G-protein linked signal transduction mechanism controls chemotaxis in eukaryotes. During development the social amoeba Dictyostelium directs chemotaxis towards external cAMP with its G-protein linked cAMP receptor. Interactions of the receptor and G-prot ... Link to item Cite

G protein-linked signal transduction in aggregating Dictyostelium.

Journal Article Society of General Physiologists series · January 1, 1990 Cite

Multiple alpha subunits of guanine nucleotide-binding proteins in Dictyostelium.

Journal Article Proc Natl Acad Sci U S A · July 1989 Previous results have shown that chemotaxis and the expression of several classes of genes in Dictyostelium discoideum are regulated through a cell surface cAMP receptor interacting with guanine nucleotide-binding proteins (G proteins). We now describe clo ... Full text Link to item Cite

G-protein-linked signal transduction systems control development in Dictyostelium.

Journal Article Development · 1989 G-protein-linked cAMP receptors play an essential role in Dictyostelium development. The cAMP receptors are proposed to have seven transmembrane domains and a cytoplasmic C-terminal region. Overexpression of the receptor in cells, when the endogenous recep ... Full text Link to item Cite

cAMP receptor and G-protein interactions control development in Dictyostelium

Journal Article Cold Spring Harbor Symposia on Quantitative Biology · 1988 Cite

Development and characterization of a monoclonal antibody to human embryonal carcinoma.

Journal Article J Urol · June 1987 A monoclonal anti-testicular carcinoma antibody was obtained via the somatic cell fusion technique by immunization of BALB/c mice with freshly prepared single cell suspension from a patient with testicular embryonal carcinoma with choriocarcinoma component ... Full text Link to item Cite