Geoffrey Stuart Pitt

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

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

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

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

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

Added benefit of mineralocorticoid receptor blockade in the primary prevention of sudden cardiac death.

Journal article Circulation · June 12, 2007 Featured Publication Full text Link to item 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