Regulation of sodium channel activity by phosphorylation

Scheuer, Todd

doi:10.1016/j.semcdb.2010.10.002

Cited by 87 publications

(88 citation statements)

References 79 publications

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“…Because increased phosphorylation in the ID I-II linker region of Nav1.2 can acutely suppress Nav1.2 currents (reviewed in Ref. 5), it is possible that decreases in phosphorylation associated with increased Nav1.2 methylation upon PRMT8 coexpression may contribute to the observed increase in current. We speculate that the increased methylation and decreased phosphorylation of mammalian brain Nav1.2 that we observed in response to acute seizures in vivo underlie the acquired increases in Nav current in neurons following a seizure or other pro-epileptic insult.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Phosphorylation of sodium channels is a critical regulator of channel activity, with phosphorylation state changing dramatically as a function of seizure activity in the brain (6,7). In the heart, CaMKII phosphorylation has been shown to enhance persistent sodium current and induce a shift in steady-state channel availability (19).…”

Section: Discussionmentioning

confidence: 99%

“…The auxiliary β-subunits and a family of FGF homologous factors (FHF) have been shown to modulate trafficking and functional properties of voltage-gated sodium channels (3)(4)(5). Both PKA and PKC have been shown to modulate neuronal voltage-gated sodium current function (6,7). Finally, intracellular calcium, calmodulin, and calcium/calmodulin protein kinase II (CaMKII) have been shown to have drastic effects on the cardiac sodium channel (8)(9)(10).…”

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confidence: 99%

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

Thompson

Hawkins

Kearney

et al. 2017

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

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Monogenic epilepsies with wide-ranging clinical severity have been associated with mutations in voltage-gated sodium channel genes. In the Scn2a Q54 mouse model of epilepsy, a focal epilepsy phenotype is caused by transgenic expression of an engineered Na V 1.2 mutation displaying enhanced persistent sodium current. Seizure frequency and other phenotypic features in Scn2a Q54 mice depend on genetic background. We investigated the neurophysiological and molecular correlates of strain-dependent epilepsy severity in this model. Scn2a Q54 mice on the C57BL/6J background (B6.Q54) exhibit a mild disorder, whereas animals intercrossed with SJL/J mice (F1.Q54) have a severe phenotype. Whole-cell recording revealed that hippocampal pyramidal neurons from B6.Q54 and F1.Q54 animals exhibit spontaneous action potentials, but F1.Q54 neurons exhibited higher firing frequency and greater evoked activity compared with B6.Q54 neurons. These findings correlated with larger persistent sodium current and depolarized inactivation in neurons from F1.Q54 animals. Because calcium/calmodulin protein kinase II (CaMKII) is known to modify persistent current and channel inactivation in the heart, we investigated CaMKII as a plausible modulator of neuronal sodium channels. CaMKII activity in hippocampal protein lysates exhibited a strain-dependence in Scn2a Q54 mice with higher activity in F1.Q54 animals. Heterologously expressed Na V 1.2 channels exposed to activated CaMKII had enhanced persistent current and depolarized channel inactivation resembling the properties of F1.Q54 neuronal sodium channels. By contrast, inhibition of CaMKII attenuated persistent current, evoked a hyperpolarized channel inactivation, and suppressed neuronal excitability. We conclude that CaMKII-mediated modulation of neuronal sodium current impacts neuronal excitability in Scn2a Q54 mice and may represent a therapeutic target for the treatment of epilepsy.epilepsy | voltage-gated sodium channel | CaMKII V oltage-gated sodium channels are essential for the generation and propagation of action potentials in excitable cells (1). These proteins exist as heteromultimeric complexes formed by a large pore-forming α-subunit and one or more auxiliary β-subunits (2). Function of voltage-gated sodium channels is influenced by multiple intracellular factors including protein-protein interactions, channel phosphorylation, and intracellular calcium. The auxiliary β-subunits and a family of FGF homologous factors (FHF) have been shown to modulate trafficking and functional properties of voltage-gated sodium channels (3-5). Both PKA and PKC have been shown to modulate neuronal voltage-gated sodium current function (6, 7). Finally, intracellular calcium, calmodulin, and calcium/calmodulin protein kinase II (CaMKII) have been shown to have drastic effects on the cardiac sodium channel (8-10). Thus, differences in posttranslational modification of sodium channels may profoundly influence the physiology of excitable cells.Mutations in genes encoding neuronal voltage-gated sodium ch...

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“…Well-documented examples of other transport proteins and channels in the distal tubule and collecting duct, which are regulated by phosphorylation, include the water channel aquaporin (17) and several sodium transport proteins (28,38). Accumulating evidence emphasizes a critical role for phosphorylation of the water channel aquaporin-2 for membrane trafficking and endosomal recycling, both as a feature of its physiological response to vasopressin as well as participation in the pathophysiological mechanism of human nephrogenic diabetes insipidus (4,18).…”

Section: Discussionmentioning

confidence: 99%

pH-dependent regulation of the α-subunit of H⁺-K⁺-ATPase (HKα₂)

Codina

Opyd

Powell

et al. 2011

American Journal of Physiology-Renal Physiology

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: 1745-1755, 2010). In the present study, we investigated the ability of chronic acidosis and GPR4 to regulate HK␣2 expression in HEK-293 cells. Chronic acidosis was modeled in vitro by using multiple methods: reducing media pH by adjusting bicarbonate concentration, adding HCl, or by increasing the ambient concentration of CO 2. PKA activity and HK␣2 protein were monitored by immunoblot analysis, and HK␣ 2 mRNA, by real-time PCR. Chronic acidosis did not alter the expression of HK␣ 2 mRNA; however, PKA activity and HK␣ 2 protein abundance increased when media pH decreased from 7.4 to 6.8. Furthermore, this increase was independent of the method used to create chronic acidosis. Heterologous expression of GPR4 was sufficient to increase both basal and acid-stimulated PKA activity and similarly increase basal and acidstimulated HK␣ 2 expression. Collectively, these results suggest that chronic acidosis and GPR4 increase HK␣ 2 protein by increasing PKA activity without altering HK␣ 2 mRNA abundance, implicating a regulatory role of pH-activated GPR4 in homeostatic regulation of HK␣ 2 and acid-base balance.

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Regulation of sodium channel activity by phosphorylation

Cited by 87 publications

References 79 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

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

pH-dependent regulation of the α-subunit of H⁺-K⁺-ATPase (HKα₂)

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Regulation of sodium channel activity by phosphorylation

Cited by 87 publications

References 79 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

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

pH-dependent regulation of the α-subunit of H+-K+-ATPase (HKα2)

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pH-dependent regulation of the α-subunit of H⁺-K⁺-ATPase (HKα₂)