Proton Modulation of Cardiac I Na: A Potential Arrhythmogenic Trigger

Jones, David K.; Ruben, Peter C.

doi:10.1007/978-3-642-41588-3_8

Cited by 14 publications

(38 citation statements)

References 82 publications

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“…Within the cardiac system, acidosis disrupts the regulation of action potential duration associated with cardiac excitability. 34 Most notably, this action potential disruption is caused by cardiac ischemia and acidosis, which impairs sodium channels and can lead to life-threatening events such as arrhythmia, myocardial infarction, and cardiac death. [35][36][37] A decrease in interstitial tissue pH may alter angiogenesis.…”

Section: Role For the Ph-sensing Gpcrs In The Cardiovascular Systemmentioning

confidence: 99%

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Sanderlin¹,

Justus²,

Krewson³

et al. 2015

CHC

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Protons (hydrogen ions) are the simplest form of ions universally produced by cellular metabolism including aerobic respiration and glycolysis. Export of protons out of cells by a number of acid transporters is essential to maintain a stable intracellular pH that is critical for normal cell function. Acid products in the tissue interstitium are removed by blood perfusion and excreted from the body through the respiratory and renal systems. However, the pH homeostasis in tissues is frequently disrupted in many pathophysiologic conditions such as in ischemic tissues and tumors where protons are overproduced and blood perfusion is compromised. Consequently, accumulation of protons causes acidosis in the affected tissue. Although acidosis has profound effects on cell function and disease progression, little is known about the molecular mechanisms by which cells sense and respond to acidotic stress. Recently a family of pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 (TDAG8), and GPR68 (OGR1), has been identified and characterized. These GPCRs can be activated by extracellular acidic pH through the protonation of histidine residues of the receptors. Upon activation by acidosis the pH-sensing GPCRs can transduce several downstream G protein pathways such as the G s , G q/11 , and G 12/13 pathways to regulate cell behavior. Studies have revealed the biological roles of the pH-sensing GPCRs in the immune, cardiovascular, respiratory, renal, skeletal, endocrine, and nervous systems, as well as the involvement of these receptors in a variety of pathological conditions such as cancer, inflammation, pain, and cardiovascular disease. As GPCRs are important drug targets, small molecule modulators of the pH-sensing GPCRs are being developed and evaluated for potential therapeutic applications in disease treatment.

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Section: Role For the Ph-sensing Gpcrs In The Cardiovascular Systemmentioning

confidence: 99%

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Sanderlin¹,

Justus²,

Krewson³

et al. 2015

CHC

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“…9). Proton block of vertebrae Na V s has been well characterized and occurs predominantly through the protonation of residues lining the extracellular vestibule above the SF 177; 178; 179 . The BacNa V structures suggest that protons might neutralize key sidechains required to coordinate and conduct Na + -water complexes through the SF or destabilize interactions required to maintain the SF in a conductive conformation.…”

Section: Introductionmentioning

confidence: 99%

Bacterial Voltage-Gated Sodium Channels (BacNaVs) from the Soil, Sea, and Salt Lakes Enlighten Molecular Mechanisms of Electrical Signaling and Pharmacology in the Brain and Heart

Payandeh¹,

Minor

2015

Journal of Molecular Biology

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Voltage-gated sodium channels (NaVs) provide the initial electrical signal that drives action potential generation in many excitable cells of the brain, heart, and nervous system. For more than 60 years, functional studies of NaVs have occupied a central place in physiological and biophysical investigation of the molecular basis of excitability. Recently, structural studies of members of a large family of bacterial voltage-gated sodium channels (BacNaVs) prevalent in soil, marine, and salt lake environments that bear many of the core features of eukaryotic NaVs have reframed ideas for voltage-gated channel function, ion selectivity, and pharmacology. Here, we analyze the recent advances, unanswered questions, and potential of BacNaVs as templates for drug development efforts.

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“…The initiation and progression of arrhythmia depend upon electrical disorders in the heart2, but the mechanisms for electrical disorder remain unclear. Ion channels, including potassium, sodium and calcium, play essential roles in arrhythmia34. When suffering with ischemic stress, the cardiomyocytes (CMs) undergo lots of changes, especially the remodeling of ion channels of sarcolemma35.…”

mentioning

confidence: 99%

Over-expression of microRNA-1 causes arrhythmia by disturbing intracellular trafficking system

Liang

Wang

et al. 2017

Sci Rep

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Dysregulation of intracellular trafficking system plays a fundamental role in the progression of cardiovascular disease. Up-regulation of miR-1 contributes to arrhythmia, we sought to elucidate whether intracellular trafficking contributes to miR-1-driven arrhythmia. By performing microarray analyses of the transcriptome in the cardiomyocytes-specific over-expression of microRNA-1 (miR-1 Tg) mice and the WT mice, we found that these differentially expressed genes in miR-1 Tg mice were significantly enrichment with the trafficking-related biological processes, such as regulation of calcium ion transport. Also, the qRT-PCR and western blot results validated that Stx6, Braf, Ube3a, Mapk8ip3, Ap1s1, Ccz1 and Gja1, which are the trafficking-related genes, were significantly down-regulated in the miR-1 Tg mice. Moreover, we found that Stx6 was decreased in the heart of mice after myocardial infarction and in the hypoxic cardiomyocytes, and further confirmed that Stx6 is a target of miR-1. Meanwhile, knockdown of Stx6 in cardiomyocytes resulted in the impairments of PLM and L-type calcium channel, which leads to the increased resting ([Ca2+]i). On the contrary, overexpression of Stx6 attenuated the impairments of miR-1 or hypoxia on PLM and L-type calcium channel. Thus, our studies reveals that trafficking-related gene Stx6 may regulate intracellular calcium and is involved in the occurrence of cardiac arrhythmia, which provides new insights in that miR-1 participates in arrhythmia by regulating the trafficking-related genes and pathway.

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Proton Modulation of Cardiac I Na: A Potential Arrhythmogenic Trigger

Cited by 14 publications

References 82 publications

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Bacterial Voltage-Gated Sodium Channels (BacNaVs) from the Soil, Sea, and Salt Lakes Enlighten Molecular Mechanisms of Electrical Signaling and Pharmacology in the Brain and Heart

Over-expression of microRNA-1 causes arrhythmia by disturbing intracellular trafficking system

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