title: CaMKII locally encodes L-type channel activity to signal to nuclear CREB in excitation-transcription coupling.
abstract: Communication between cell surface proteins and the nucleus is integral to many cellular adaptations. In the case of ion channels in excitable cells, the dynamics of signaling to the nucleus are particularly important because the natural stimulus, surface membrane depolarization, is rapidly pulsatile. To better understand excitation-transcription coupling we characterized the dependence of cAMP response element-binding protein phosphorylation, a critical step in neuronal plasticity, on the level and duration of membrane depolarization. We find that signaling strength is steeply dependent on depolarization, with sensitivity far greater than hitherto recognized. In contrast, graded blockade of the Ca(2+) channel pore has a remarkably mild effect, although some Ca(2+) entry is absolutely required. Our data indicate that Ca(2+)/CaM-dependent protein kinase II acting near the channel couples local Ca(2+) rises to signal transduction, encoding the frequency of Ca(2+) channel openings rather than integrated Ca(2+) flux-a form of digital logic.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Damian G
authors.initials: DG
authors.lastname: Wheeler
authors.forename: Curtis F
authors.initials: CF
authors.lastname: Barrett
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Groth
authors.forename: Parsa
authors.initials: P
authors.lastname: Safa
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tsien
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D008564:Membrane Potentials; D009474:Neurons / Q000201:enzymology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: C508137:Creb1 protein, rat; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C517658:CAMK2B protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517675:Camk2a protein, rat; D002118:Calcium