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CaMKII locally encodes L-type channel activity to signal to nuclear CREB in excitation–transcription coupling

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305

Correspondence to Richard W. Tsien: rwtsien{at}stanford.edu

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 Ca²⁺ channel pore has a remarkably mild effect, although some Ca²⁺ entry is absolutely required. Our data indicate that Ca²⁺/CaM-dependent protein kinase II acting near the channel couples local Ca²⁺ rises to signal transduction, encoding the frequency of Ca²⁺ channel openings rather than integrated Ca²⁺ flux—a form of digital logic.

C.F. Barrett's present address is Dept. of Neurology and Dept. of Human Genetics, Leiden University Medical Centre, 2300 RC Leiden, Netherlands.

Abbreviations used in this paper: CaMKII, Ca²⁺/CaM-dependent protein kinase II; CREB, cAMP response element–binding protein; E-C, excitation–contraction; E-S, excitation–secretion; E-T, excitation–transcription; i_Ca, unitary Ca²⁺ flux; pCREB, Ser¹³³-phospho-CREB; P_o, open probability; RyR, ryanodine receptor; SCG, superior cervical ganglion; shRNA, short hairpin RNA; TTX, tetrodotoxin.

© 2008 Wheeler et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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• Wheeler, D. G., Barrett, C. F., Groth, R. D., Safa, P., Tsien, R. W. (2008). CaMKII locally encodes L-type channel activity to signal to nuclear CREB in excitation-transcription coupling. JGP 133: i2-i2 [Full Text]  

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