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

Geoffrey W. Abbott^*, Margaret H. Butler and Steve A. N. Goldstein^,1

^* Greenberg Division of Cardiology, Department of Medicine and Department of Pharmacology, Cornell University, Weill Medical College, New York, New York, USA; and
Department of Pediatrics and The Institute of Molecular Pediatric Sciences, University of Chicago, Pritzker School of Medicine, Chicago, Illinois, USA

¹ Correspondence: Department of Pediatrics and The Institute of Molecular Pediatric Sciences, University of Chicago, Pritzker School of Medicine, 5721 S. Maryland Ave., MC8000 (K160), Chicago, IL 60637, USA. E-mail: sangoldstein{at}uchicago.edu

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 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.—Abbott, G. W., Butler, M. H., Goldstein, S. A. N. Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2-Kv3.4 potassium channels in periodic paralysis.

Key Words: KCNE3 • periodic paralysis • MiRP2 • Kv3.4

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