Related Experiment Videos
Voltage-gated channels block nicotinic regulation of CREB phosphorylation and gene expression in neurons
1Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Abstract:
Synaptic activation of the transcription factor CREB and downstream gene expression usually depend on calcium influx aided by voltage-gated calcium channels. We find that nicotinic signaling, in contrast, activates CREB and gene expression in ciliary ganglion neurons both in culture and in situ only if voltage-gated channels are silent. The nicotinic response requires calcium influx and release from internal stores and acts through CaMK and MAPK pathways to sustain activated CREB. Voltage-gated channels mobilize CaMK to activate CREB initially, but they also enable calcineurin and PP1 to terminate the activation before transcription is affected. L-type voltage-gated channels dominate the outcome and block the effects of nicotinic signaling on transcription. This demonstrates a novel aspect of activity-dependent gene regulation.
Insights
Nicotinic signaling activates CREB and gene expression in neurons, but only when voltage-gated calcium channels are inactive. These channels normally block this pathway, highlighting a new form of activity-dependent gene regulation.
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Signaling
Background:
- Synaptic activation of CREB (cAMP response element-binding protein) and gene expression typically relies on calcium influx via voltage-gated calcium channels.
- Understanding the regulation of CREB activation is crucial for deciphering neuronal plasticity and function.
Purpose of the Study:
- To investigate the role of nicotinic signaling in CREB activation and gene expression in ciliary ganglion neurons.
- To determine the interplay between nicotinic signaling and voltage-gated calcium channels in regulating CREB activity.
Main Methods:
- Experiments were conducted on ciliary ganglion neurons both in culture and in situ.
- Investigated calcium influx, release from internal stores, and the involvement of CaMK and MAPK pathways.
- Manipulated voltage-gated calcium channel activity to assess its impact on nicotinic signaling pathways.
Main Results:
- Nicotinic signaling activates CREB and gene expression independently of voltage-gated calcium channels when these channels are silent.
- The nicotinic pathway requires calcium influx and release from internal stores, engaging CaMK and MAPK.
- Voltage-gated calcium channels initially activate CREB but also trigger calcineurin and PP1 to terminate activation, thereby blocking nicotinic effects on transcription, particularly L-type channels.
Conclusions:
- Nicotinic signaling provides an alternative pathway for CREB activation and gene expression in neurons.
- Voltage-gated calcium channels act as a gatekeeper, inhibiting nicotinic-driven transcription by promoting CREB deactivation.
- This study reveals a novel mechanism of activity-dependent gene regulation distinct from canonical pathways.