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

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.