Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2‐Kv3.4 potassium channels in periodic paralysis

Abbott, Geoffrey W.; Butler, Margaret H.; Goldstein, Steve A.N.

doi:10.1096/fj.05-5070com

Cited by 40 publications

(33 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is interesting that the action of A␤ was not limited to the poreforming K V 3.4 subunit. Indeed, it also induced an overexpression of MIRP2, a neuronal ␤-subunit coassembling with K V 3.4 subunit and playing a crucial role in the control of its biophysical properties and pharmacological profile (Abbott et al, 2001(Abbott et al, , 2006. Such MIRP2 overexpression might profoundly interfere with the function of pore-forming K V 3.4 ␣-subunits, suggesting that the neurotoxic A␤ peptide might influence the I A current by modulating simultaneously the pore-forming ␣-subunit and its accessory component expression.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, K V 3.4 subunits can form stable complexes with MinK-related peptide 2 (MIRP2). Such an interaction modifies the voltage-dependence of activation, speeds the recovery from inactivation, reduces the cumulative inactivation, and finally, affects unitary conductance of K V 3.4 channels (Abbott et al, 2001(Abbott et al, , 2006. In addition, K V 3.4 channel subunits can form heteromeric channels by coassembling with other members of the K V 3 subfamily, such as K V 3.1, K V 3.2, and K V 3.3 channel subunits (Rudy et al, 1999;Rudy and McBain, 2001).…”

Section: Alteration Of Neuronal Kmentioning

confidence: 99%

See 1 more Smart Citation

Up-Regulation and Increased Activity of KV3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death

Pannaccione¹,

Boscia²,

Scorziello³

et al. 2007

Molecular Pharmacology

View full text Add to dashboard Cite

The aim of the present study was to investigate whether K V 3.4 channel subunits are involved in neuronal death induced by neurotoxic ␤-amyloid peptides (A␤). In particular, to test this hypothesis, three main questions were addressed: 1) whether the A␤ peptide can up-regulate both the transcription/translation and activity of K V 3.4 channel subunit and its accessory subunit, MinK-related peptide 2 (MIRP2); 2) whether the increase in K V 3.4 expression and activity can be mediated by the nuclear factor-B (NF-B) family of transcriptional factors; and 3) whether the specific inhibition of K V 3.4 channel subunit reverts the A␤ peptide-induced neurodegeneration in hippocampal neurons and nerve growth factor (NGF)-differentiated PC-12 cells. We found that A␤ 1-42 treatment induced an increase in K V 3.4 and MIRP2 transcripts and proteins, detected by reverse transcription-polymerase chain reaction and Western blot analysis, respectively, in NGF-differentiated PC-12 cells and hippocampal neurons. Patch-clamp experiments performed in whole-cell configuration revealed that the A␤ peptide caused an increase in I A current amplitude carried by K V 3.4 channel subunits, as revealed by their specific blockade with blood depressing substance-I (BDS-I) in both hippocampal neurons and NGF-differentiated PC-12 cells. The inhibition of NF-B nuclear translocation with the cell membrane-permeable peptide SN-50 prevented the increase in K V 3.4 protein and transcript expression. In addition, the SN-50 peptide was able to block A␤ 1-42 -induced increase in K V 3.4 K ϩ currents and to prevent cell death caused by A␤ 1-42 exposure. Finally, BDS-I produced a similar neuroprotective effect by inhibiting the increase in K V 3.4 expression. As a whole, our data indicate that K V 3.4 channels could be a novel target for Alzheimer's disease pharmacological therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Alteration Of Neuronal Kmentioning

confidence: 99%

Up-Regulation and Increased Activity of KV3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death

Pannaccione¹,

Boscia²,

Scorziello³

et al. 2007

Molecular Pharmacology

View full text Add to dashboard Cite

show abstract

“…This is associated with periodic paralysis, a channelopathy characterized by skeletal muscle dysfunction, leading to attacks of paralysis lasting from hours to days (Abbott et al, 2001). The MiRP2-Kv3.4 complex is highly regulated by protein kinase C-phosphorylation of the Kv3.4 inactivation domain disrupts its ordered structure and its ability to inactivate the channel (Antz et al, 1999); constitutive phosphorylation of serine 82 on MiRP2 is required for its modulatory effects on Kv3.4 (Abbott et al, 2006). Thus, global dephosphorylation of MiRP2 and Kv3.4 reduces current by positive-shifting activation and speeding inactivation; when phosphorylated, the channel complex can activate at more negative voltages and inactivates much more slowly, increasing overall current.…”

mentioning

confidence: 99%

The MiRP2-Kv3.4 Potassium Channel: Muscling In on Alzheimer’s Disease

Choi¹,

Abbott²

2007

Molecular Pharmacology

Self Cite

View full text Add to dashboard Cite

In this issue of Molecular Pharmacology (p. 665), Pannacione et al. provide evidence of a role for the voltage-gated potassium channel ␣ subunit Kv3.4 and its ancillary subunit MiRP2 in ␤-amyloid (A␤) peptide-mediated neuronal death. The MiRP2-Kv3.4 channel complex-previously found to be important in skeletal myocyte physiology-is now argued to be a molecular correlate of the transient outward potassium current up-regulated by A␤ peptide, considered a significant step in the etiology of Alzheimer's disease. The authors conclude that MiRP2 and Kv3.4 are up-regulated by A␤ peptide in a nuclear factor B-dependent fashion at the transcriptional level, and the sea anemone toxin BDS-I is shown to protect against A␤ peptidemediated cell death by specific blockade of Kv3.4-generated current. The findings lend weight to the premise that specific channels, such as MiRP2-Kv3.4, could hold promise as future therapeutic targets in Alzheimer's disease and potentially other neurodegenerative disorders.The etiology of Alzheimer's disease (AD) remains unknown. Pathological hallmarks include cortical neuron loss, proteinaceous senile plaques, and neurofibrillary tangles. According to the ␤-amyloid (or A␤) hypothesis, A␤ peptide-the main constituent of plaques-is considered to be linked to the selective neurodegeneration seen in AD. Although much progress has been made in characterizing the neurotoxic effects of A␤, the mechanism by which it induces neuronal death remains unknown (Pallà s and Camins, 2006).Potassium ion (K ϩ ) efflux is a critical step in the apoptosis of many cell types in response to a range of proapoptotic stimuli (Yu, 2003). Recent evidence points to an increase in voltage-gated potassium (Kv) channel current in the etiology of A␤-induced neuronal apoptosis; however, the molecular mechanism by which K ϩ current is up-regulated and the subunit identity of the Kv channels involved are still under debate (see below). Kv channel pore-forming (␣) subunits are generated by a numerous and functionally diverse family of genes, with ϳ40 known members in the human genome.Each ␣ subunit contains six transmembrane domains, a voltage sensor, and pore elements; four ␣ subunits coassemble to form the functional tetramer. In vivo, Kv channels are each regulated by a host of possible non-pore-forming subunits with either cytoplasmic or transmembrane disposition; some are regulatory proteins that also modulate other protein types; others are dedicated Kv channel ancillary subunits (McCrossan and Abbott, 2004).Although mutations in several Kv channel ␣ and ancillary subunit genes are associated with inherited human diseases-referred to as "channelopathies"-the massive number of different Kv channel subtypes that can potentially arise from the matrix of possible ␣-␣ and ␣-ancillary subunit interactions has thus far hampered identification of the precise molecular entities in the large majority of both physiological Kv currents and suspected Kv channel-related disorders.AD is no exception. Ramsden et al. (2001) noted that ...

show abstract

“…However, whether this is a pathogenic mutation or a benign polymorphism remains to be established, with up to 15 to 20% of PP cases being negative for genetic testing for known SCN4A and CACNA1S mutations, thus other loci are undoubtedly linked to PP. 2,14 Fourth and finally, others have found reduced inward-rectifying ATP-sensitive K ϩ -channel (K ATP ) current in muscle biopsies of patients with PP. These channels are metabolically regulated, have a high density in many tissues (e.g., pancreatic islet cells), and are closely regulated by hormones, such as insulin, which provide an attractive hypothesis to explain the link between PP attacks and carbohydrate intake.…”

Section: Periodic Paralysismentioning

confidence: 99%

Treatment of Neuromuscular Channelopathies: Current Concepts and Future Prospects

Cleland

Griggs

2008

Neurotherapeutics

View full text Add to dashboard Cite

Summary:Our understanding of the molecular pathogenesis of the neuromuscular ion channelopathies has increased rapidly over the past two decades due to the identification of many of the genes whose mutation causes these diseases. These molecular discoveries have facilitated identification and classification of the hereditary periodic paralyses and the myotonias, and are likely to shed light on acquired ion channelopathies as well. Despite our better understanding of the pathogenesis of these disorders, current treatments are largely empirical and the evidence in favor of specific therapy largely anecdotal. For periodic paralysis, dichlorphenamide-a carbonic anhydrase inhibitor-has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis. A second trial, comparing dichlorphenamide with acetazolamide versus placebo, is currently in progress. For myotonia, there is only anecdotal evidence for treatment, but a controlled trial of mexiletine versus placebo is currently being funded by a Food and Drug Administration-orphan products grant and is scheduled to begin in late 2008. In the future, mechanism-based approaches are likely to be developed. For example, exciting advances have already been made in one disorder, myotonic dystrophy-1 (DM-1). In a mouse model of DM-1, a morpholino antisense oligonucleuotide targeting the 3= splice site of CLCN1 exon 7a repaired the RNA splicing defect by promoting the production of full-length chloride channel transcripts. Abnormal chloride conductance was restored, and myotonia was abolished. Similar strategies hold potential for DM-2. The era of molecularly-based treatments is about to begin.

show abstract

Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2‐Kv3.4 potassium channels in periodic paralysis

Cited by 40 publications

References 48 publications

Up-Regulation and Increased Activity of KV3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death

Up-Regulation and Increased Activity of KV3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death

The MiRP2-Kv3.4 Potassium Channel: Muscling In on Alzheimer’s Disease

Treatment of Neuromuscular Channelopathies: Current Concepts and Future Prospects

Contact Info

Product

Resources

About