Differential subunit composition of the G protein–activated inward-rectifier potassium channel during cardiac development

Fleischmann, Bernd K.; Duan, Yaqi; Fan, Yun; Schöneberg, Torsten; Ehlich, Andreas; Lenka, Nibedita; Viatchenko‐Karpinski, Serge; Pott, Lutz; Hescheler, Juergen; Fakler, Bernd

doi:10.1172/jci200415925

Cited by 35 publications

(19 citation statements)

References 39 publications

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“…To confirm the electrophysiological phenotype at the molecular level, we analyzed RNA samples from control and Grem2‐treated cells at differentiation days 8 and 10. The results showed that Grem2 induced genes that encode atrial contractile proteins ( Myl7 or Mlc2a ) , gap junction proteins ( Gja5 ) , and ion channels ( Kcnj5 , Cacna1d ) , as well as Nppa and Sarcolipin (Fig. C; Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

Gremlin 2 Promotes Differentiation of Embryonic Stem Cells to Atrial Fate by Activation of the JNK Signaling Pathway

Tanwar¹,

Bylund

Hu³

et al. 2014

Stem Cells

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The Bone Morphogenetic Protein antagonist Gremlin 2 (Grem2) is required for atrial differentiation and establishment of cardiac rhythm during embryonic development. A human Grem2 variant has been associated with familial atrial fibrillation, suggesting that abnormal Grem2 activity causes arrhythmias. However, it is not known how Grem2 integrates into signaling pathways to direct atrial cardiomyocyte differentiation. Here, we demonstrate that Grem2 expression is induced concurrently with the emergence of cardiovascular progenitor cells during differentiation of mouse embryonic (ES) stem cells. Grem2 exposure enhances the cardiogenic potential of ES cells by ~20–120 fold, preferentially inducing genes expressed in atrial myocytes such as Myl7, Nppa and Sarcolipin. We show that Grem2 acts upstream to upregulate pro-atrial transcriptional factors CoupTFII and Hey1 and downregulate atrial fate repressors Irx4 and Hey2. The molecular phenotype of Grem2-induced atrial cardiomyocytes was further supported by induction of ion channels encoded by Kcnj3, Kcnj5, and Cacna1D genes and establishment of atrial-like action potentials shown by electrophysiological recordings. We show that promotion of atrial-like cardiomyocyte is specific to the Gremlin subfamily of BMP antagonists. Grem2 pro-atrial differentiation activity is conveyed by non-canonical BMP signaling through phosphorylation of JNK and can be reversed by specific JNK inhibitors, but not by dorsomorphin, an inhibitor of canonical BMP signaling. Taken together, our data provide novel mechanistic insights into atrial cardiomyocyte differentiation from pluripotent stem cells and will assist the development of future approaches to study and treat arrhythmias.

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Section: Resultsmentioning

confidence: 99%

Gremlin 2 Promotes Differentiation of Embryonic Stem Cells to Atrial Fate by Activation of the JNK Signaling Pathway

Tanwar¹,

Bylund

Hu³

et al. 2014

Stem Cells

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“…In case of the embryonic chick heart, the subunit composition has not been studied yet. In the embryonic mouse heart, Kir3 subunit composition has been shown to undergo developmental changes (Fleischmann et al 2004). These authors suggest a developmental increase in homomeric Kir3.4 channel from an early to the late embryonic stage.…”

Section: Discussionmentioning

confidence: 99%

Generation of a constitutive Na⁺‐dependent inward‐rectifier current in rat adult atrial myocytes by overexpression of Kir3.4

Mintert

Bösche

Rinne

et al. 2007

The Journal of Physiology

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Apart from gating by interaction with betagamma subunits from heterotrimeric G proteins upon stimulation of appropriate receptors, Kir.3 channels have been shown to be gated by intracellular Na+. However, no information is available on how Na+-dependent gating affects endogenous Kir3.1/Kir3.4 channels in mammalian atrial myocytes. We therefore studied how loading of adult atrial myocytes from rat hearts via the patch pipette filling solution with different concentrations of Na+ ([Na+]pip) affects Kir3 current. Surprisingly, in a range between 0 and 60 mm, Na+ neither had an effect on basal inward-rectifier current nor on the current activated by acetylcholine. Overexpression of Kir3.4 in adult atrial myocytes forced by adenoviral gene transfer results in formation of functional homomeric channels that interact with betagamma subunits upon activation of endogenous muscarinic receptors. These channels are activated at [Na+]pip >or= 15 mm, resulting in a receptor-independent basal inward rectifier current (I bir). I bir was neither affected by pertussis toxin nor by GDP-beta-S, suggesting G-protein-independent activation. PIP(2) depletion via endogenous PLC-coupled alpha1 adrenergic receptors causes inhibition of endogenous Kir3.1/3.4 channel currents by about 75%. In contrast, inhibition of Na+-activated I bir amounts to < 20%. The effect of the Kir3 channel blocker tertiapin-Q can be described using an IC50 of 12 nm (endogenous I K(ACh)) and 0.61 nm (I bir). These data clearly identify I bir as a homotetrameric Kir3.4 channel current with novel properties of regulation and pharmacology. Ibir shares some properties with a basal current recently described in atrial myocytes from an animal model of atrial fibrillation (AF) and AF patients.

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“…Similar to Gβ 2 , Gβ 4 is known to influence the activity of the cardiac GIRK channel, which regulates the heart rhythm through the acetylcholine-dependent activation of the muscarinic M2-receptor present in the sinoatrial node [107][108][109][110]. Although this gene has been reported in human hereditary neuropathy, genome-wide association studies have revealed association of the GNB4 locus with variation in heart rate [47,111,112].…”

Section: G Protein Subunit Beta (Gnb4 Gβ 4 )mentioning

confidence: 99%

The Emerging Role of Gβ Subunits in Human Genetic Diseases

Malerba

Nittis

Merla

2019

Cells

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Environmental stimuli are perceived and transduced inside the cell through the activation of signaling pathways. One common type of cell signaling transduction network is initiated by G-proteins. G-proteins are activated by G-protein-coupled receptors (GPCRs) and transmit signals from hormones, neurotransmitters, and other signaling factors, thus controlling a number of biological processes that include synaptic transmission, visual photoreception, hormone and growth factors release, regulation of cell contraction and migration, as well as cell growth and differentiation. G-proteins mainly act as heterotrimeric complexes, composed of alpha, beta, and gamma subunits. In the last few years, whole exome sequencing and biochemical studies have shown causality of disease-causing variants in genes encoding G-proteins and human genetic diseases. This review focuses on the G-protein β subunits and their emerging role in the etiology of genetically inherited rare diseases in humans.

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Differential subunit composition of the G protein–activated inward-rectifier potassium channel during cardiac development

Cited by 35 publications

References 39 publications

Gremlin 2 Promotes Differentiation of Embryonic Stem Cells to Atrial Fate by Activation of the JNK Signaling Pathway

Gremlin 2 Promotes Differentiation of Embryonic Stem Cells to Atrial Fate by Activation of the JNK Signaling Pathway

Generation of a constitutive Na⁺‐dependent inward‐rectifier current in rat adult atrial myocytes by overexpression of Kir3.4

The Emerging Role of Gβ Subunits in Human Genetic Diseases

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Differential subunit composition of the G protein–activated inward-rectifier potassium channel during cardiac development

Cited by 35 publications

References 39 publications

Gremlin 2 Promotes Differentiation of Embryonic Stem Cells to Atrial Fate by Activation of the JNK Signaling Pathway

Gremlin 2 Promotes Differentiation of Embryonic Stem Cells to Atrial Fate by Activation of the JNK Signaling Pathway

Generation of a constitutive Na+‐dependent inward‐rectifier current in rat adult atrial myocytes by overexpression of Kir3.4

The Emerging Role of Gβ Subunits in Human Genetic Diseases

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Generation of a constitutive Na⁺‐dependent inward‐rectifier current in rat adult atrial myocytes by overexpression of Kir3.4