Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2‐Kv3.4 potassium channels in periodic paralysis
| العنوان: | Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2‐Kv3.4 potassium channels in periodic paralysis |
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| المؤلفون: | Geoffrey W. Abbott, Steve A.N. Goldstein, Margaret H. Butler |
| المصدر: | The FASEB Journal. 20:293-301 |
| بيانات النشر: | Wiley, 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Intracellular pH, Molecular Sequence Data, PKC Phosphorylation Site, Biochemistry, Cell Line, Paralyses, Familial Periodic, Serine, Cricetinae, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Phosphorylation, Molecular Biology, Conserved Sequence, Protein kinase C, Binding Sites, Chemistry, KCNE3, Periodic paralysis, medicine.disease, Potassium channel, Protein Structure, Tertiary, Shaw Potassium Channels, Potassium Channels, Voltage-Gated, Mutation, Biophysics, Protons, Ion Channel Gating, Biotechnology |
| الوصف: | MinK-related peptide 2 (MiRP2) and Kv3.4 subunits assemble in skeletal muscle to create subthreshold, voltage-gated potassium channels. MiRP2 acts on Kv3.4 to shift the voltage dependence of activation, speed recovery from inactivation, suppress cumulative inactivation and increase unitary conductance. We previously found an R83H missense mutation in MiRP2 that segregated with periodic paralysis in two families and diminished the effects of MiRP2 on Kv3.4. Here we show that MiRP2 has a single, functional PKC phosphorylation site at serine 82 and that normal MiRP2-Kv3.4 function requires phosphorylation of the site. The R83H variant does not prevent PKC phosphorylation of neighboring S82; rather, the change shifts the voltage dependence of activation and endows MiRP2-Kv3.4 channels with sensitivity to changes in intracellular pH across the physiological range. Thus, current passed by single R83H channels decreases as internal pH is lowered (pK(a) approximately 7.3, consistent with histidine protonation) whereas wild-type channels are largely insensitive. These findings identify a key regulatory domain in MiRP2 and suggest a mechanistic link between acidosis and episodes of periodic paralysis. |
| تدمد: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.05-5070com |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e36a6729caccb9ea8e1d428827beca12 https://doi.org/10.1096/fj.05-5070com |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e36a6729caccb9ea8e1d428827beca12 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15306860 08926638 |
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| DOI: | 10.1096/fj.05-5070com |