Signaling from Synapse to Nuclear Gene Transcription

How does a neuron keep track of how active it has been in order to adapt accordingly? Postsynaptic Ca2+ channels are well suited for this task because they send signals to the nucleus to control transcription factors and downstream gene expression. Over the last 15 years, our lab has worked on activity-dependent regulation of CREB and NFAT, two transcription factors of importance for changing the relative abundance of many neuronal proteins. We study excitation-transcription coupling because of a biophysical interest in voltage-dependent processes, harkening back to ion channel gating, and a cell biological fascination with how information is conveyed over a distance. While some scientists believe that diffusion of Ca2+ to nuclear enzymes is sufficient to account for signaling from surface membrane to nucleus, our evidence favors the idea that Ca2+ emanating from L-type channels acts locally to cause changes in phosphorylation state of protein components, that then travel to the nucleus. Characterizing the “black-box” features of this system (steep voltage-dependence; bell-shaped frequency dependence) has led to a partial understanding of the underlying mechanisms. Changes in the pattern of neuronal gene expression must ultimately be related to the role of individual neurons in information processing. Transcriptional regulation in the nucleus must be coordinated with local changes in protein translation, in dendrites and possibly axons as well.


Related Publications

25 MAY 2012

Cav1 and Cav2 Channels Engage Distinct Modes of Ca2+ Signaling to Control CREB-Dependent Gene Expression · Damian G. Wheeler, Rachel D. Groth, Huan Ma, Curtis F. Barrett, Scott F. Owen, Parsa Safa, Richard W. Tsien · 2012 · Cell 149(5):1112-24

Activity-dependent gene expression triggered by Ca2+ entry into neurons is critical for learning and memory, but whether specific sources of Ca2+ act distinctly or supply to a common pool was uncertain. We found that voltage-dependent-gated Cav1 channels use the Ca2+ nanodomain to drive local CaMKII aggregation and trigger communication with the nucleus. In contrast, Cav2 channels must elevate Ca2+ concentration microns away and promote CaMKII aggregation at Cav1 channels, making them less efficient in signaling to the nucleus.


CaMKII locally encodes L-type channel activity to signal to nuclear CREB in excitation-transcription coupling · Damian G. Wheeler, Curtis F. Barrett, Rachel D. Groth, Parsa Safa, Richard W. Tsien · 2008 · Journal of Cell Biology 183(5):849-63

The dynamics of signaling from ion channels to the nucleus in excitable cells is dependent on pulsatile membrane depolarizations. To better understantd excitation-transcription coupling, we characterized the dependence of cAMP response element-binding phosphorylation on the level and duration of membrane depolarization. We found that signaling strength is steeply dependent on depolarization, and 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 the Ca2+ flux.