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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<jats:italic>in vivo<\/jats:italic>, and brief glutamate stimulation of cultured hippocampal neurons.<jats:italic>In vitro<\/jats:italic>calcineurin digestion shows that supersensitivity of S603 dephosphorylation is an inherent property of Kv2.1. Conversely, suppression of neuronal activity by anesthetic<jats:italic>in vivo<\/jats:italic>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.<\/jats:p>","DOI":"10.1523\/jneurosci.3970-06.2006","type":"journal-article","created":{"date-parts":[[2006,12,27]],"date-time":"2006-12-27T17:24:22Z","timestamp":1167240262000},"page":"13505-13514","source":"Crossref","is-referenced-by-count":102,"title":["Bidirectional Activity-Dependent Regulation of Neuronal Ion Channel Phosphorylation"],"prefix":"10.1523","volume":"26","author":[{"given":"Hiroaki","family":"Misonou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Menegola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Durga P.","family":"Mohapatra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren K.","family":"Guy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang-Sik","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"Trimmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2006,12,27]]},"reference":[{"key":"2023041303223908000_26.52.13505.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(01)00476-6"},{"key":"2023041303223908000_26.52.13505.2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.t01-2-00611.x"},{"key":"2023041303223908000_26.52.13505.3","doi-asserted-by":"crossref","first-page":"7258","DOI":"10.1523\/JNEUROSCI.20-19-07258.2000","article-title":"Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins","volume":"20","author":"Chung","year":"2000","journal-title":"J Neurosci"},{"key":"2023041303223908000_26.52.13505.4","doi-asserted-by":"publisher","DOI":"10.1038\/nn857"},{"key":"2023041303223908000_26.52.13505.5","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(94)90425-1"},{"key":"2023041303223908000_26.52.13505.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.t01-2-00019.xm"},{"key":"2023041303223908000_26.52.13505.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)00129-X"},{"key":"2023041303223908000_26.52.13505.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2005.08.018"},{"key":"2023041303223908000_26.52.13505.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.06.006"},{"key":"2023041303223908000_26.52.13505.10","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1152\/jn.2000.83.1.70","article-title":"Voltage-gated potassium channels activated during action potentials in layer V neocortical pyramidal neurons","volume":"83","author":"Kang","year":"2000","journal-title":"J Neurophysiol"},{"key":"2023041303223908000_26.52.13505.11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.00621.x"},{"key":"2023041303223908000_26.52.13505.12","doi-asserted-by":"publisher","DOI":"10.1038\/nn1647"},{"key":"2023041303223908000_26.52.13505.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2004.07.068"},{"key":"2023041303223908000_26.52.13505.14","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80902-2"},{"key":"2023041303223908000_26.52.13505.15","doi-asserted-by":"crossref","first-page":"3840","DOI":"10.1523\/JNEUROSCI.15-05-03840.1995","article-title":"Differential spatiotemporal expression of K+ channel polypeptides in rat hippocampal neurons developing in situ and in vitro","volume":"15","author":"Maletic-Savatic","year":"1995","journal-title":"J Neurosci"},{"key":"2023041303223908000_26.52.13505.16","doi-asserted-by":"crossref","first-page":"5191","DOI":"10.1523\/JNEUROSCI.20-14-05191.2000","article-title":"Elimination of the fast transient in superior cervical ganglion neurons with expression of KV4.2W362F: molecular dissection of IA","volume":"20","author":"Malin","year":"2000","journal-title":"J Neurosci"},{"key":"2023041303223908000_26.52.13505.17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1997.593ba.x"},{"key":"2023041303223908000_26.52.13505.18","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/j.1432-1033.1995.317_c.x","article-title":"Different susceptibility of protein kinases to staurosporine inhibition. 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