Paroxysms of excitement: sodium channel dysfunction in heart and brain

Head, Cathy; Gardiner, Mark

doi:10.1002/bies.10338

Cited by 9 publications

(9 citation statements)

References 68 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A number of SCN5A mutations in different affected individuals/families have been identified ( Fig. 3A) and linked to Brugada syndrome and to conduction defects, in addition to LQT3 (23,36,51,60,93,102,105,204,253,422,519,525,540). Interestingly, mutations in noncardiac Nav channel genes have also been linked to familial paroxysmal dysfunction in the skeletal and nervous systems (123,204,220,359).…”

Section: A Voltage-gated Na ؉ (Nav) Currentsmentioning

confidence: 99%

“…These differences contribute to the normal unidirectional propagation of excitation through the myocardium and to the generation of normal cardiac rhythms (23,24,259,374,375). Changes in the properties or the functional expression of myocardial ion channels, resulting from inherited mutations in the genes encoding these channels (23,36,51,102,204,243,253) or from myocardial disease (34,49,67,184,365,496,(501)(502)(503)510), can lead to changes in action potential waveforms, synchronization, and/or propagation, thereby predisposing the heart to potentially life-threatening arrhythmias (13,14,16,24,127,259,436). There is, therefore, considerable interest in delineating the molecular, cellular, and systemic mechanisms contributing to the generation and maintenance of normal cardiac rhythms, as well as in understanding how these mechanisms are altered in the diseased myocardium.…”

Section: Introductionmentioning

confidence: 99%

“…It also has now been shown that mutations in the genes encoding the subunits involved in the generation of functional cardiac Nav, Kv, Cav, and Kir channels underlie several inherited cardiac arrhythmias (23,36,51,102,204,253,479,481). Although inherited rhythm disorders are rare, these mutations belong to an ever-increasing number of "channelopathies," i.e., diseases linked to genes encoding ion channels (35,123,204,220,234,243,267,309,359,403,442,459). Based on the rapid progression of this field (249) and the growing molecular complexity of ion channels, it seems certain that the number of genes encoding ion channels or ion channel regulatory molecules linked to inherited and acquired disorders of the cardiovascular (and other) system will continue to increase, perhaps dramatically, in the future.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular Physiology of Cardiac Repolarization

Nerbonne¹,

Kass²

2005

Physiological Reviews

886

940

View full text Add to dashboard Cite

The heart is a rhythmic electromechanical pump, the functioning of which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until the next impulse is generated. Myocardial action potentials reflect the sequential activation and inactivation of inward (Na(+) and Ca(2+)) and outward (K(+)) current carrying ion channels. In different regions of the heart, action potential waveforms are distinct, owing to differences in Na(+), Ca(2+), and K(+) channel expression, and these differences contribute to the normal, unidirectional propagation of activity and to the generation of normal cardiac rhythms. Changes in channel functioning, resulting from inherited or acquired disease, affect action potential repolarization and can lead to the generation of life-threatening arrhythmias. There is, therefore, considerable interest in understanding the mechanisms that control cardiac repolarization and rhythm generation. Electrophysiological studies have detailed the properties of the Na(+), Ca(2+), and K(+) currents that generate cardiac action potentials, and molecular cloning has revealed a large number of pore forming (alpha) and accessory (beta, delta, and gamma) subunits thought to contribute to the formation of these channels. Considerable progress has been made in defining the functional roles of the various channels and in identifying the alpha-subunits encoding these channels. Much less is known, however, about the functioning of channel accessory subunits and/or posttranslational processing of the channel proteins. It has also become clear that cardiac ion channels function as components of macromolecular complexes, comprising the alpha-subunits, one or more accessory subunit, and a variety of other regulatory proteins. In addition, these macromolecular channel protein complexes appear to interact with the actin cytoskeleton and/or the extracellular matrix, suggesting important functional links between channel complexes, as well as between cardiac structure and electrical functioning. Important areas of future research will be the identification of (all of) the molecular components of functional cardiac ion channels and delineation of the molecular mechanisms involved in regulating the expression and the functioning of these channels in the normal and the diseased myocardium.

show abstract

Section: A Voltage-gated Na ؉ (Nav) Currentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Physiology of Cardiac Repolarization

Nerbonne¹,

Kass²

2005

Physiological Reviews

886

940

View full text Add to dashboard Cite

show abstract

“…Cardiac channelopathies, including arrhythmias such as the long QT syndrome 3, Brugada syndrome, progressive cardiac conduction defect, and familial nonprogressive conduction defect have been linked to mutations in Na v 1.5 (Head and Gardiner, 2003). Finally, the demonstration that VGSC subtypes such as Na v 1.3, Na v 1.7, Na v 1.8, and Na v 1.9 are involved in pain pathways has made them attractive targets for the development of novel therapeutic strategies for pain treatment (Julius and Basbaum, 2001;Nassar et al, 2004).…”

mentioning

confidence: 99%

Four Novel Tarantula Toxins as Selective Modulators of Voltage-Gated Sodium Channel Subtypes

Bosmans¹,

Rash²,

Zhu³

et al. 2005

Mol Pharmacol

141

131

View full text Add to dashboard Cite

Four novel peptide toxins that act on voltage-gated sodium channels have been isolated from tarantula venoms: ceratotoxins 1, 2, and 3 (CcoTx1, CcoTx2, and CcoTx3) from Ceratogyrus cornuatus and phrixotoxin 3 (PaurTx3) from Phrixotrichus auratus. The pharmacological profiles of these new toxins were characterized by electrophysiological measurements on six cloned voltage-gated sodium channel subtypes expressed in Xenopus laevis oocytes

show abstract

“…Activation and inactivation properties of these channels are crucial for determining normal nerve function and muscle contraction. Perhaps the most dramatic illustration of the changes wrought by slight modifications to the activation and inactivation properties are the human diseases caused by mutations that produce myotonias or cardiac arrest (Head & Gardiner, 2003; Goldin, 2003). Mutations in the human sodium channels that disturb activation and/or inactivation are widely distributed over the primary sequence, indicating that many regions of the channel are capable of influencing activation and inactivation.…”

mentioning

confidence: 99%

Modulation of skeletal and cardiac voltage‐gated sodium channels by calmodulin

Young

Caldwell

2005

The Journal of Physiology

View full text Add to dashboard Cite

Calmodulin (CaM) has been shown to modulate different ion channels, including voltage-gated sodium channels (NaChs). Using the yeast two-hybrid assay, we found an interaction between CaM and the C-terminal domains of adult skeletal (Na V 1.4) and cardiac (Na V 1.5) muscle NaChs. Effects of CaM were studied using sodium channels transiently expressed in CHO cells. Wild type CaM (CaM WT ) caused a hyperpolarizing shift in the voltage dependence of activation and inactivation for Na V 1.4 and activation for Na V 1.5. Intracellular application of CaM caused hyperpolarizing shifts equivalent to those seen with CaM WT coexpression with Na V 1.4. Elevated Ca 2+ and CaM-binding peptides caused depolarizing shifts in the inactivation curves seen with CaM WT coexpression with Na V 1.4. KN93, a CaM-kinase II inhibitor, had no effect on Na V 1.4, suggesting that CaM acts directly on Na V 1.4 and not through activation of CaM-kinase II. Coexpression of hemi-mutant CaMs showed that an intact N-terminal lobe of CaM is required for effects of CaM upon Na V 1.4. Mutations in the sodium channel IQ domain disrupted the effects of CaM on Na V 1.4: the I1727E mutation completely blocked all calmodulin effects, while the L1736R mutation disrupted the effects of Ca 2+ -calmodulin on inactivation. Chimeric channels of Na V 1.4 and Na V 1.5 also indicated that the C-terminal domain is largely responsible for CaM effects on inactivation. CaM had little effect on Na V 1.4 expressed in HEK cells, possibly due to large differences in the endogenous expression of β-subunits between CHO and HEK cells. These results in heterologous cells suggest that Ca 2+ released during muscle contraction rapidly modulates NaCh availability via CaM.

show abstract

Paroxysms of excitement: sodium channel dysfunction in heart and brain

Cited by 9 publications

References 68 publications

Molecular Physiology of Cardiac Repolarization

Molecular Physiology of Cardiac Repolarization

Four Novel Tarantula Toxins as Selective Modulators of Voltage-Gated Sodium Channel Subtypes

Modulation of skeletal and cardiac voltage‐gated sodium channels by calmodulin

Contact Info

Product

Resources

About