Bidirectional activity-dependent regulation of neuronal ion channel phosphorylation

Hiroaki Misonou, Milena Menegola, Durga P. Mohapatra, Lauren K. Guy, Kang Sik Park, James S. Trimmer

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


Activity-dependent dephosphorylation of neuronal Kv2.1 channels yields hyperpolarizing shifts in their voltage-dependent activation and homoeostatic suppression of neuronal excitability. We recently identified 16 phosphorylation sites that modulate Kv2.1 function. Here, we show that in mammalian neurons, compared with other regulated sites, such as serine (S)563, phosphorylation at S603 is supersensitive to calcineurin-mediated dephosphorylation in response to kainate-induced seizures in vivo, and brief glutamate stimulation of cultured hippocampal neurons. In vitro calcineurin digestion shows that supersensitivity of S603 dephosphorylation is an inherent property of Kv2.1. Conversely, suppression of neuronal activity by anesthetic in vivo causes hyperphosphorylation at S603 but not S563. Distinct regulation of individual phosphorylation sites allows for graded and bidirectional homeostatic regulation of Kv2.1 function. S603 phosphorylation represents a sensitive bidirectional biosensor of neuronal activity.

Original languageEnglish
Pages (from-to)13505-13514
Number of pages10
JournalJournal of Neuroscience
Issue number52
StatePublished - Dec 27 2006


  • Calcineurin
  • Calcium
  • Hippocampus
  • Intracellular signaling
  • Kv2.1
  • Potassium channel


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