Signal Transduction Mechanisms by Which Ca2+ Regulates Adaptive Neuronal Responses

Abstract:
Extracellular stimuli elicit a variety of cellular responses that are critical for differentiation and survival during the development of the nervous system and for the adaptive responses of the mature nervous system. The goal of our research is to identify the signal transduction pathways that mediate the responses of cells in the developing and mature nervous system to neurotrophic factors and neurotransmitters. Recent studies that will be discussed have defined specific signaling pathways by which extracellular Ca ²⁺ entering neurons via the L-type voltage sensitive Ca ²⁺ channel induces brain derived neurotrophic factor (BDNF) transcription. Three key regulatory regions within BDNF promoter III have been characterized and two of the transcription factors that bind to these sequences have been defined. One of the factors that mediates Ca ²⁺ regulation of BDNF transcription is a novel transcription factor that is distinct from previously characterized transcriptional regulators. The second factor is the Ca ²⁺ /cAMP regulatory element binding protein (CREB). We find that Ca ²⁺ induces CREB phosphorylation at multiple sites which may confer Ca ²⁺ selectivity and neuronal specificity to the BDNF transcriptional response. These new insights into the mechanisms by which Ca ²⁺ influx triggers BDNF transcription may provide a basis for understanding how Ca ²⁺ influx mediates neuronal responses in the developing and mature nervous system.