Protein arginine methyl transferases‐3 and ‐5 increase cell surface expression of cardiac sodium channel

Beltrán-Álvarez, Pedro; Espejo, Alexsandra; Schmauder, Ralf; Beltrán, Carlos; Mrowka, Ralf; Linke, Thomas; Batlle, Montserrat; Pérez‐Villa, Félix; Pérez, Guillermo J.; Scornik, Fabiana S.; Benndorf, Klaus; Pagans, Sara; Zimmer, Thomas; Brugada, Ramón

doi:10.1016/j.febslet.2013.07.043

Cited by 42 publications

(34 citation statements)

References 29 publications

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“…These results are consistent with increased methylation resulting in enhanced amplitude of Nav current. In the case of Nav1.5, the authors presented data supporting increased cell surface expression of Nav1.5 channels as a mechanism contributing to the increased Nav current (54). We found in samples from mammalian brain that increased arginine methylation was associated with decreases in Nav1.2 phosphorylation.…”

Section: Discussionsupporting

confidence: 57%

Reciprocal Changes in Phosphorylation and Methylation of Mammalian Brain Sodium Channels in Response to Seizures

Baek

Rubinstein

Scheuer

et al. 2014

Journal of Biological Chemistry

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Background: Sodium channels underlie neuronal excitability and are regulated by seizures. Results: Mass spectrometric analysis of brain sodium channels revealed novel phosphorylation and methylation sites that decreased and increased, respectively, after seizures. Inducing methylation increased sodium channel activity. Conclusion: Reciprocal phosphorylation and methylation after seizures will alter sodium channel function. Significance: Such regulation would impact neuronal excitability.

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Section: Discussionsupporting

confidence: 57%

Reciprocal Changes in Phosphorylation and Methylation of Mammalian Brain Sodium Channels in Response to Seizures

Baek

Rubinstein

Scheuer

et al. 2014

Journal of Biological Chemistry

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“…Previous studies have suggested that methylation of some ion channel proteins could affect their activities/functions (Beltran-Alvarez et al, 2013; Sariban-Sohraby et al, 1984). To investigate a potential interaction between KCNQ2 and Prmt1, co-immunoprecipitation experiments were conducted with HEK293T cells.…”

Section: Resultsmentioning

confidence: 99%

Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression

Kim

Jeong

Kim

et al. 2016

eLife

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KCNQ channels are critical determinants of neuronal excitability, thus emerging as a novel target of anti-epileptic drugs. To date, the mechanisms of KCNQ channel modulation have been mostly characterized to be inhibitory via Gq-coupled receptors, Ca2+/CaM, and protein kinase C. Here we demonstrate that methylation of KCNQ by protein arginine methyltransferase 1 (Prmt1) positively regulates KCNQ channel activity, thereby preventing neuronal hyperexcitability. Prmt1+/- mice exhibit epileptic seizures. Methylation of KCNQ2 channels at 4 arginine residues by Prmt1 enhances PIP2 binding, and Prmt1 depletion lowers PIP2 affinity of KCNQ2 channels and thereby the channel activities. Consistently, exogenous PIP2 addition to Prmt1+/- neurons restores KCNQ currents and neuronal excitability to the WT level. Collectively, we propose that Prmt1-dependent facilitation of KCNQ-PIP2 interaction underlies the positive regulation of KCNQ activity by arginine methylation, which may serve as a key target for prevention of neuronal hyperexcitability and seizures.DOI: http://dx.doi.org/10.7554/eLife.17159.001

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“…5, A and B), six are associated with the plasma membrane, including the strongest binder, NHERF2. Importantly, PRMT5 has been shown to methylate a number of proteins that are membraneassociated (37,38). We thus surmised that the C terminus of PRMT5 was responsible for localizing it to the intracellular side of the plasma membrane.…”

Section: -3-3/pdz Switchingmentioning

confidence: 99%

PRMT5 C-terminal Phosphorylation Modulates a 14-3-3/PDZ Interaction Switch

Espejo

Gao

Black

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuPRMT5 is the primary enzyme responsible for the deposition of the symmetric dimethylarginine in mammalian cells. In an effort to understand how PRMT5 is regulated, we identified a threonine phosphorylation site within a C-terminal tail motif, which is targeted by the Akt/serum-and glucocorticoid-inducible kinases. While investigating the function of this posttranslational modification, we serendipitously discovered that its free C-terminal tail binds PDZ domains (when unphosphorylated) and 14-3-3 proteins (when phosphorylated). In essence, a phosphorylation event within the last few residues of the C-terminal tail generates a posttranslational modification-dependent PDZ/ 14-3-3 interaction "switch." The C-terminal motif of PRMT5 is required for plasma membrane association, and loss of this switching capacity is not compatible with life. This signaling phenomenon was recently reported for the HPV E6 oncoprotein but has not yet been observed for mammalian proteins. To investigate the prevalence of PDZ/14-3-3 switching in signal transduction, we built a protein domain microarray that harbors PDZ domains and 14-3-3 proteins. We have used this microarray to interrogate the C-terminal tails of a small group of candidate proteins and identified ERBB4, PGHS2, and IRK1 (as well as E6 and PRMT5) as conforming to this signaling mode, suggesting that PDZ/14-3-3 switching may be a broad biological paradigm.Arginine methylation is a common PTM 3 that alters roughly 0.5% of all arginine residues in the cells. There are three types of arginine methylation: monomethylarginine, asymmetric dimethylarginine, and symmetric dimethylarginine (1). PRMT5 is one of nine PRMTs, and it is responsible for the vast majority (Ͼ95%) of the symmetric dimethylarginine modifications (2). PRMT5 was first characterized as a transcriptional repressor for cyclin E1 (3), and in this context, it methylates histone H3R8me2s, H2AR3me2s, and H4R3me2s (4). An epigenetic silencing role for PRMT5 has also recently been reported for the cell cycle inhibitor p21 (5).However, PRMT5 clearly has a number of non-histone substrates that are localized to the cytoplasm and the plasma membrane (6). In the cytoplasm, PRMT5 forms part of the methylosome and methylates a number of splicing factors (7). In keeping with these observations, the conditional deletion of PRMT5 in neural stem cells leads to defects in the core splicing machinery, reduced constitutive splicing, and massive alterations in alternative splicing profiles (8). Thus, this arginine methyltransferase has key biological roles that are associated with each of the major cellular compartments (the nucleus, the cytoplasm, and the plasma membrane), although little is known about how the activity and localization of PRMT5 in these different compartments are regulated.There is an emerging interest in establishing how signal transduction pathways communicate with chromatin and regulate changes to the epigenetic landscapes (9). It is likely that enzymes like PRMT5 may be marked by different ...

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Protein arginine methyl transferases‐3 and ‐5 increase cell surface expression of cardiac sodium channel

Cited by 42 publications

References 29 publications

Reciprocal Changes in Phosphorylation and Methylation of Mammalian Brain Sodium Channels in Response to Seizures

Reciprocal Changes in Phosphorylation and Methylation of Mammalian Brain Sodium Channels in Response to Seizures

Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression

PRMT5 C-terminal Phosphorylation Modulates a 14-3-3/PDZ Interaction Switch

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