Bidirectional activity-dependent regulation of neuronal ion channel phosphorylation.
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.
Misonou
Hiroaki
H
Department of Pharmacology, School of Medicine, University of California, Davis, California 95616, USA.
Menegola
Milena
M
Mohapatra
Durga P
DP
Guy
Lauren K
LK
Park
Kang-Sik
KS
Trimmer
James S
JS
D000818:Animals; D002478:Cells, Cultured; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007473:Ion Channels / Q000819:agonists / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010424:Pentobarbital / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D051669:Shab Potassium Channels / Q000819:agonists / Q000502:physiology
D007473:Ion Channels; D051669:Shab Potassium Channels; D010424:Pentobarbital; D007608:Kainic Acid