Pharmacological correction of long QT-linked mutations in <i>KCNH2</i> (<i>hERG</i>) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum

Smith, Jennifer L.; Reloj, Allison R.; Nataraj, Parvathi; Bartos, Daniel C.; Schroder, Elizabeth A.; Moss, Arthur J.; Ohno, Seiko; Horie, Minoru; Anderson, Corey L.; January, Craig T.; Delisle, Brian P.

doi:10.1152/ajpcell.00406.2012

Cited by 32 publications

(44 citation statements)

References 44 publications

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“…; Smith et al . ). Although the transitional ER compartment contains ER exit sites from which COPII vesicles bud off for transport to the Golgi apparatus, the mutant K V 11.1 channels do not undergo ER export because they are excluded from the ER exit sites.…”

Section: Trafficking and Sequestration Of K+ Channelsmentioning

confidence: 97%

Potassium channels in the heart: structure, function and regulation

Grandi

Sanguinetti

Bartos

et al. 2016

The Journal of Physiology

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This paper is the outcome of the fourth UC Davis Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias Symposium, a biannual event that aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2016 symposium was 'K Channels and Regulation'. Experts in the field contributed their experimental and mathematical modelling perspectives and discussed emerging questions, controversies and challenges on the topic of cardiac K channels. This paper summarizes the topics of formal presentations and informal discussions from the symposium on the structural basis of voltage-gated K channel function, as well as the mechanisms involved in regulation of K channel gating, expression and membrane localization. Given the critical role for K channels in determining the rate of cardiac repolarization, it is hardly surprising that essentially every aspect of K channel function is exquisitely regulated in cardiac myocytes. This regulation is complex and highly interrelated to other aspects of myocardial function. K channel regulatory mechanisms alter, and are altered by, physiological challenges, pathophysiological conditions, and pharmacological agents. An accompanying paper focuses on the integrative role of K channels in cardiac electrophysiology, i.e. how K currents shape the cardiac action potential, and how their dysfunction can lead to arrhythmias, and discusses K channel-based therapeutics. A fundamental understanding of K channel regulatory mechanisms and disease processes is fundamental to reveal new targets for human therapy.

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Section: Trafficking and Sequestration Of K+ Channelsmentioning

confidence: 97%

Potassium channels in the heart: structure, function and regulation

Grandi

Sanguinetti

Bartos

et al. 2016

The Journal of Physiology

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“…mutants occurs [79]. Because it is not required that most PCs be present during protein synthesis, previously synthesized pools of target proteins can be rescued [53,80–82].…”

Section: Cotranslational Vs Post Translational Modificationmentioning

confidence: 99%

“…Once PCs have induced native-like structures that permit their target proteins to pass the ER quality control system, these proteins are trafficked to their functional destination and the presence of the PC appears to no longer be required [83]. Thus, the duration of PC exposure that is necessary to rescue a protein is usually far shorter than the half-life of its target protein [79,83], a phenomenon of clinical importance (see section 5.2).…”

Section: Cotranslational Vs Post Translational Modificationmentioning

confidence: 99%

“…Because most PCs are effective chaperones of accumulated pools of non-natively folded proteins and because the PC exposure time required for chaperoning is far shorter than the half-life of the chaperoned protein [79,83], intermittent (pulsatile) PC administration may provide PC-free periods during which chaperoned protein can be active, provided PC dissociation occurs. Such an approach may be particularly useful in the case of lysosomal storage disorders where substrate reduction is the objective.…”

Section: Pharmacology Of Pcsmentioning

confidence: 99%

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Pharmacological chaperoning: A primer on mechanism and pharmacology

Leidenheimer

Ryder

2014

Pharmacological Research

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Approximately forty percent of diseases are attributable to protein misfolding, including those for which genetic mutation produces misfolding mutants. Intriguingly, many of these mutants are not terminally misfolded since native-like folding, and subsequent trafficking to functional locations, can be induced by target-specific, small molecules variably termed pharmacological chaperones, pharmacoperones, or pharmacochaperones (PCs). PC targets include enzymes, receptors, transporters, and ion channels, revealing the breadth of proteins that can be engaged by ligand-assisted folding. The purpose of this review is to provide an integrated primer of the diverse mechanisms and pharmacology of PCs. In this regard, we examine the structural mechanisms that underlie PC rescue of misfolding mutants, including the ability of PCs to act as surrogates for defective intramolecular interactions and, at the intermolecular level, overcome oligomerization deficiencies and dominant negative effects, as well as influence the subunit stoichiometry of heteropentameric receptors. Not surprisingly, PC-mediated structural correction of misfolding mutants normalizes interactions with molecular chaperones that participate in protein quality control and forward-trafficking. A variety of small molecules have proven to be efficacious PCs and the advantages and disadvantages of employing orthostatic antagonists, active-site inhibitors, orthostatic agonists, and allosteric modulator PCs is considered. Also examined is the possibility that several therapeutic agents may have unrecognized activity as PCs, and this chaperoning activity may mediate/contribute to therapeutic action and/or account for adverse effects. Lastly, we explore evidence that pharmacological chaperoning exploits intrinsic ligand-assisted folding mechanisms. Given the widespread applicability of PC rescue of mutants associated with protein folding disorders, both in vitro and in vivo, the therapeutic potential of PCs is vast. This is most evident in the treatment of lysosomal storage disorders, cystic fibrosis, and nephrogenic diabetes insipidus, for which proof of principle in humans has been demonstrated.

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“…The use of PCs has become a great promise as a novel therapeutic alternative for the treatment of protein folding disorders (Leidenheimer and Ryder, 2014).It is believed that most PCs such as nicotine affect various ER compartments post-translationally (Akaike et al, 2010;Smith et al, 2013). PCs induce nativelike structures that let their target proteins pass the ER control system.…”

Section: Nicotine; Pharmacological Chaperone Of Nachrsmentioning

confidence: 99%