Signaling to the Nucleus by an L-type Calcium Channel-Calmodulin Complex Through the MAP Kinase Pathway

TLDR

Calcium entry, especially through L‑type voltage‑activated channels, activates signaling pathways that drive expression of genes essential for dendritic development, neuronal survival, and synaptic plasticity. The study aimed to develop a functional knock‑in method to identify LTC features that couple calcium entry to gene‑expression pathways. A functional knock‑in approach was used to probe LTC domains that link calcium entry to transcriptional signaling. An IQ motif in the LTC’s C‑terminus that binds Ca²⁺‑calmodulin is essential for transmitting the calcium signal to the nucleus via Ras/MAPK activation, with CaM acting as a local sensor that drives expression of genes supporting neuronal survival and plasticity.

Abstract

Increases in the intracellular concentration of calcium ([Ca 2+ ] i ) activate various signaling pathways that lead to the expression of genes that are essential for dendritic development, neuronal survival, and synaptic plasticity. The mode of Ca 2+ entry into a neuron plays a key role in determining which signaling pathways are activated and thus specifies the cellular response to Ca 2+ . Ca 2+ influx through L-type voltage-activated channels (LTCs) is particularly effective at activating transcription factors such as CREB and MEF-2. We developed a functional knock-in technique to investigate the features of LTCs that specifically couple them to the signaling pathways that regulate gene expression. We found that an isoleucine-glutamine (“IQ”) motif in the carboxyl terminus of the LTC that binds Ca 2+ -calmodulin (CaM) is critical for conveying the Ca 2+ signal to the nucleus. Ca 2+ -CaM binding to the LTC was necessary for activation of the Ras/mitogen-activated protein kinase (MAPK) pathway, which conveys local Ca 2+ signals from the mouth of the LTC to the nucleus. CaM functions as a local Ca 2+ sensor at the mouth of the LTC that activates the MAPK pathway and leads to the stimulation of genes that are essential for neuronal survival and plasticity.