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

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.