Phosphorylation and Putative ER Retention Signals Are Required for Protein Kinase A-Mediated Potentiation of Cardiac Sodium Current

Zhou, Jingsong; Shin, Hyeon-Gyu; Yi, Jianxun; Shen, Wangzhen; Williams, Christine P.; Murray, Katherine T.

doi:10.1161/01.res.0000033598.00903.27

Cited by 80 publications

(73 citation statements)

References 44 publications

(58 reference statements)

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“…These data suggest that RAS activation altered Na ϩ channel transcription but that there was posttranscriptional compensation in our model. Examples of posttranscriptional Na ϩ channel modulation include protein kinase A-mediated phosphorylation effects that can enhance channel current (62), and gating changes similar to those we observed have been noted with protein kinase A and C activation (34,42). Among the possible explanations for the discrepancy between mRNA abundance and current are increased translational efficiency and reduced channel degradation.…”

Section: Discussionsupporting

confidence: 74%

Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation

Kasi

Xiao

Shang

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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(RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrioHisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac Na ϩ channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type Ca 2ϩ channel, Kv4.2 K ϩ channel ␣-subunit, and Cx45 mRNA abundances and the peak ventricular Na ϩ current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as heart failure.peptidyl-dipeptidase A; angiotensin II; heart block ARRHYTHMIC SUDDEN DEATH is a common terminal event in various cardiomyopathies and end-stage heart failure. Upregulation of the renin-angiotensin system (RAS) has been implicated in risk of sudden death in these conditions. A critical component of this system is angiotensin-converting enzyme (ACE), which produces the eight-amino acid peptide angiotensin II (ANG II), a major effector peptide of the RAS. In humans, increased ANG II levels are associated with an increased risk of arrhythmia (2), which is reduced by use of ACE inhibitors or ANG II receptor blockers (4,13,20,23,27,30,49).A number of ion-handling protein changes have been posited to underlie the increase in risk of arrhythmia in states of RAS activation, and ANG II is known to act on a number of these proteins (3, 41). For example, ANG II has been implicated in Na ϩ -K ϩ pump regulation (24). Furthermore, ANG II inhibits the Ca 2ϩ -activated K ϩ current in vascular smooth muscle cells (51) and the delayed rectifier K ϩ currents in heart and...

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Section: Discussionsupporting

confidence: 74%

Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation

Kasi

Xiao

Shang

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…These treatments have been reported to inhibit RXR-mediated ER retention through PKC-or PKA-dependent receptor phosphorylation (7,19). However we were unable to observe, by immunostaining and FAC analysis, enhanced surface expression of Tac-G5/2b after either treatment.…”

Section: Fig 5 Mapping Additional Sequence Determinants For Er Retecontrasting

confidence: 83%

Cell Surface Expression of GluR5 Kainate Receptors Is Regulated by an Endoplasmic Reticulum Retention Signal

Ren¹,

Riley²,

Needleman

et al. 2003

Journal of Biological Chemistry

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Kainate receptors (KARs) are mediators of excitatory neurotransmission in the mammalian central nervous system, and their efficient targeting and trafficking is critical for normal synaptic function. A key step in the delivery of KARs to the neuronal plasma membrane is the exit of newly assembled receptors from the endoplasmic reticulum (ER). Here we report the identification of a novel ER retention signal in the alternatively spliced C-terminal domain of the GluR5-2b subunit, which controls receptor trafficking in both heterologous cells and neurons. The ER retention motif consists of a critical arginine (Arg-896) and surrounding amino acids, disruption of which promotes ER exit and surface expression of the receptors, as well as altering their physiological properties. The Arg-896-mediated ER retention of GluR5 is regulated by a mutation that mimics phosphorylation of Thr-898, but not by PDZ interactions. Furthermore, two positively charged residues (Arg-900 and Lys-901) in the C terminus were also found to regulate ER export of the receptors. Taken together, our results identify novel trafficking signals in the Cterminal domain of GluR5-2b and demonstrate that alternative splicing is an important mechanism regulating KAR function.Kainate, NMDA, 1 and AMPA receptors mediate glutamatergic excitatory neurotransmission in the mammalian central nervous system (1, 2). The intracellular trafficking and surface delivery of multimeric transmembrane proteins, such as kainate receptors, are likely to be tightly controlled processes requiring proper folding and assembly of constituent subunits, so that only fully assembled, functional receptors can be expressed on the plasma membrane. The endoplasmic reticulum (ER) is the primary checkpoint for these complex events (3). Recently, we demonstrated that an arginine-rich ER retention signal controls the ER egress and surface expression of KA2 kainate receptor subunits (4).Alternative splicing and RNA editing of ionotropic glutamate receptors have been shown to play important roles in receptor assembly and trafficking (5-8). In particular, an RXR (where R is arginine and X a large neutral or positively charged residue) motif was found in the alternatively spliced C1 cassette in the C terminus of NMDA receptor NR1 subunit, mediating the intracellular retention of most C1-containing NR1 isoforms (6, 7). Furthermore, this RXR-mediated ER retention was regulated by protein kinase C (PKC) phosphorylation (6) and a type I PDZ (postsynaptic density-95/Disc large/zona occludens-1)-binding motif in the alternate C2Ј splice cassette (6, 7). In addition, arginine 607 (Arg-607) at a Q/R (glutamine/arginine) mRNA editing site has been reported to determine the ER retention of GluR2 AMPA receptor subunits in cultured neurons (8).The GluR5 kainate receptor subunit also undergoes alternative splicing and RNA editing. Alternative splicing of the Nterminal region of the rat GluR5 mRNA yields two different isoforms, GluR5-1 and GluR5-2, where GluR5-1 contains an extra 15 amino acids compared wi...

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“…24,29 In addition, GPD1-L may affect protein kinase A-dependent phosphorylation of the channel, which blocks retention signals in the endoplasmic reticulum. 30,31 Third, oxidation state has been shown to play a role in ion channel function and the arrhythmogenesis of atrial fibrillation. 32,33 Thus, modulation via NAD ϩ /NADH levels within the cell may contribute to what is already an increasingly complex picture of cardiac sodium channel regulation.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Characterization of Novel Glycerol-3-Phosphate Dehydrogenase 1–Like Gene ( GPD1-L ) Mutations in Sudden Infant Death Syndrome

et al. 2007

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Background-Autopsy-negative sudden unexplained death, including sudden infant death syndrome, can be caused by cardiac channelopathies such as Brugada syndrome (BrS). Type 1 BrS, caused by mutations in the SCN5A-encoded sodium channel, accounts for Ϸ20% of BrS. Recently, a novel mutation in the glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) disrupted trafficking of SCN5A in a multigenerational family with BrS. We hypothesized that mutations in GPD1-L may be responsible for some cases of sudden unexplained death/sudden infant death syndrome. Methods and Results-Using denaturing high-performance liquid chromatography and direct DNA sequencing, we performed comprehensive open-reading frame/splice site mutational analysis of GPD1-L on genomic DNA extracted from necropsy tissue of 83 unrelated cases of sudden unexplained death (26 females, 57 males; average age, 14.6Ϯ10.7 years; range, 1 month to 48 years). A putative, sudden unexplained death-associated GPD1-L missense mutation, E83K, was discovered in a 3-month-old white boy. Further mutational analysis was then performed on genomic DNA derived from a population-based cohort of 221 anonymous cases of sudden infant death syndrome (84 females, 137 males; average age, 3Ϯ2 months; range, 3 days to 12 months), revealing 2 additional mutations, I124V and R273C, in a 5-week-old white girl and a 1-month-old white boy, respectively. All mutations occurred in highly conserved residues and were absent in 600 reference alleles. Compared with wild-type GPD1-L, GPD1-L mutations coexpressed with SCN5A in heterologous HEK cells produced a significantly reduced sodium current (PϽ0.01). Adenovirus-mediated gene transfer of the E83K-GPD1-L mutation into neonatal mouse myocytes markedly attenuated the sodium current (PϽ0.01). These decreases in current density are consistent with sodium channel loss-of-function diseases like BrS. Conclusions-The present study is the first to report mutations in GPD1-L as a pathogenic cause for a small subset of sudden infant death syndrome via a secondary loss-of-function mechanism whereby perturbations in GPD1-L precipitate a marked decrease in the peak sodium current and a potentially lethal BrS-like proarrhythmic substrate. (Circulation.

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Phosphorylation and Putative ER Retention Signals Are Required for Protein Kinase A-Mediated Potentiation of Cardiac Sodium Current

Cited by 80 publications

References 44 publications

Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation

Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation

Cell Surface Expression of GluR5 Kainate Receptors Is Regulated by an Endoplasmic Reticulum Retention Signal

Molecular and Functional Characterization of Novel Glycerol-3-Phosphate Dehydrogenase 1–Like Gene ( GPD1-L ) Mutations in Sudden Infant Death Syndrome

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