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

Baek, Je Hyun; Rubinstein, Moran; Scheuer, Todd; Trimmer, James S.

doi:10.1074/jbc.m114.562785

Cited by 51 publications

(65 citation statements)

References 53 publications

(52 reference statements)

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“…phosphorylation-dependent regulation of channel activity (Surti et al, 2005;Baek et al, 2014;Verdoucq et al, 2014). Based on these results, we hypothesized that phosphorylation of amino acids in the transmembrane domain causes SLAC1 activation in the CO 2 response and performed site-directed mutagenesis experiments with transgenic plants.…”

Section: Discussionmentioning

confidence: 99%

The Transmembrane Region of Guard Cell SLAC1 Channels Perceives CO₂ Signals via an ABA-Independent Pathway in Arabidopsis

et al. 2016

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The guard cell S-type anion channel, SLOW ANION CHANNEL1 (SLAC1), a key component in the control of stomatal movements, is activated in response to CO 2 and abscisic acid (ABA). Several amino acids existing in the N-terminal region of SLAC1 are involved in regulating its activity via phosphorylation in the ABA response. However, little is known about sites involved in CO 2 signal perception. To dissect sites that are necessary for the stomatal CO 2 response, we performed slac1 complementation experiments using transgenic plants expressing truncated SLAC1 proteins. Measurements of gas exchange and stomatal apertures in the truncated transgenic lines in response to CO 2 and ABA revealed that sites involved in the stomatal CO 2 response exist in the transmembrane region and do not require the SLAC1 N and C termini. CO 2 and ABA regulation of S-type anion channel activity in guard cells of the transgenic lines confirmed these results. In vivo sitedirected mutagenesis experiments targeted to amino acids within the transmembrane region of SLAC1 raise the possibility that two tyrosine residues exposed on the membrane are involved in the stomatal CO 2 response.

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Section: Discussionmentioning

confidence: 99%

The Transmembrane Region of Guard Cell SLAC1 Channels Perceives CO₂ Signals via an ABA-Independent Pathway in Arabidopsis

et al. 2016

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“…104 Beyond studies of individual PTMs, advances have been made in the study of interactions between PTMs. Baek et al 105 described downregulated phosphorylation of the brain sodium channel Nav1.2 after kainite-induced seizures with concomitant upregulated methylation at adjacent sites, which suggested reciprocal regulation of these 2 PTMs. In the specific context of histones, Garske and colleagues 104 used a MALDI-TOF (matrix-assisted laser desorption/ionization TOF) MS approach to demonstrate novel chromatin phosphorylation and methylation sites that interact with each other and mediate binding of chromatin binding proteins such as histone H3.…”

Section: The Promise Of Proteomicsmentioning

confidence: 99%

Transformative Impact of Proteomics on Cardiovascular Health and Disease

Lindsey¹,

Mayr²,

Gomes³

et al. 2015

Circulation

143

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Abstract-The year 2014 marked the 20th anniversary of the coining of the term proteomics. The purpose of this scientific statement is to summarize advances over this period that have catalyzed our capacity to address the experimental, translational, and clinical implications of proteomics as applied to cardiovascular health and disease and to evaluate the current status of the field. Key successes that have energized the field are delineated; opportunities for proteomics to drive basic science research, facilitate clinical translation, and establish diagnostic and therapeutic healthcare algorithms are discussed; and challenges that remain to be solved before proteomic technologies can be readily translated from scientific discoveries to meaningful advances in cardiovascular care are addressed. Proteomics is the result of disruptive technologies, namely, mass spectrometry and database searching, which drove protein analysis from 1 protein at a time to protein mixture analyses that enable large-scale analysis of proteins and facilitate paradigm shifts in biological concepts that address important clinical questions. Over the past 20 years, the field of proteomics has matured, yet it is still developing rapidly. The scope of this statement will extend beyond the reaches of a typical review article and offer guidance on the use of next-generation proteomics for future scientific discovery in the basic research laboratory and clinical settings.

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“…Ion channels, especially voltage-gated channels, are critically regulated by phosphorylation. Voltage-dependent sodium and potassium channels have been shown to be the target of multiple phosphorylation events, regulating different channel functions and being involved in pathological states, like epilepsy (7)(8)(9)(10)(11). Also, several studies have shown the crucial role of the L-type/Cav1 phosphorylation in important physiological functions, like the fight or flight response (12)(13)(14)(15).…”

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confidence: 99%

Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties

Blesneac

Chemin

Bidaud

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Phosphorylation is a major mechanism regulating the activity of ion channels that remains poorly understood with respect to T-type calcium channels (Cav3). These channels are low voltage-activated calcium channels that play a key role in cellular excitability and various physiological functions. Their dysfunction has been linked to several neurological disorders, including absence epilepsy and neuropathic pain. Recent studies have revealed that T-type channels are modulated by a variety of serine/threonine protein kinase pathways, which indicates the need for a systematic analysis of T-type channel phosphorylation. Here, we immunopurified Cav3.2 channels from rat brain, and we used high-resolution MS to construct the first, to our knowledge, in vivo phosphorylation map of a voltage-gated calcium channel in a mammalian brain. We identified as many as 34 phosphorylation sites, and we show that the vast majority of these sites are also phosphorylated on the human Cav3.2 expressed in HEK293T cells. In patch-clamp studies, treatment of the channel with alkaline phosphatase as well as analysis of dephosphomimetic mutants revealed that phosphorylation regulates important functional properties of Cav3.2 channels, including voltage-dependent activation and inactivation and kinetics. We also identified that the phosphorylation of a locus situated in the loop I-II S442/S445/T446 is crucial for this regulation. Our data show that Cav3.2 channels are highly phosphorylated in the mammalian brain and establish phosphorylation as an important mechanism involved in the dynamic regulation of Cav3.2 channel gating properties.T-type calcium channel | Cav3.2 subunit | patch clamp | mass spectrometry | phosphorylation V oltage-gated calcium channels (L-, N-, P/Q-, R-, and T-types) mediate calcium entry in many different cell types in response to membrane depolarization and action potentials. Calcium influx through these channels serves as an important second messenger of electrical signaling, initiating a variety of cellular events and physiological functions (1, 2). Among the family of voltage-gated calcium channels, T-type calcium channels (Cav3 family) have unique electrophysiological properties, because they display low voltageactivated calcium currents with rapid activation/inactivation kinetics. In neurons, small changes in the membrane potential near the resting potential can activate T-type channels, favoring further membrane depolarization and repetitive firing of action potentials (3-5). These unique gating properties of T-type channels make them important in many different processes, including neuronal spontaneous firing and pacemaker activities, rebound burst firing, sleep rhythms, sensory processing, and neuronal differentiation, as well as in pathological conditions, such as epilepsy and neuropathic pain (6).To properly assure this plurality of physiological functions, a tight control of T-type calcium channels is necessary. An important regulatory mechanism is phosphorylation, the fastest and most frequent posttranslat...

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

Cited by 51 publications

References 53 publications

The Transmembrane Region of Guard Cell SLAC1 Channels Perceives CO₂ Signals via an ABA-Independent Pathway in Arabidopsis

The Transmembrane Region of Guard Cell SLAC1 Channels Perceives CO₂ Signals via an ABA-Independent Pathway in Arabidopsis

Transformative Impact of Proteomics on Cardiovascular Health and Disease

Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties

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

Cited by 51 publications

References 53 publications

The Transmembrane Region of Guard Cell SLAC1 Channels Perceives CO2 Signals via an ABA-Independent Pathway in Arabidopsis

The Transmembrane Region of Guard Cell SLAC1 Channels Perceives CO2 Signals via an ABA-Independent Pathway in Arabidopsis

Transformative Impact of Proteomics on Cardiovascular Health and Disease

Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties

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The Transmembrane Region of Guard Cell SLAC1 Channels Perceives CO₂ Signals via an ABA-Independent Pathway in Arabidopsis

The Transmembrane Region of Guard Cell SLAC1 Channels Perceives CO₂ Signals via an ABA-Independent Pathway in Arabidopsis