The multifaceted role of calcium signaling dynamics in neural cell proliferation and gliomagenesis

Abstract

Calcium (Ca2+) signaling plays a pivotal role in coordinating neural stem cell (NSC) proliferation across various cell cycle stages, regulating immediate early gene transcription, and governing processes like quiescence and cell division. Additionally, calcium signaling pathways are implicated in the initiation, progression, and therapeutic targeting of glioblastoma multiforme (GBM), particularly focusing on glioma stem cells (GSCs). Intracellular calcium levels are increased through the activation of channels, transporters, and calcium-binding proteins (CaBPs), which generate specific calcium signals characterized by spatial, temporal, and intensity profiles. Moreover, extracellular factors such as growth factors, neurotransmitters, and extracellular nucleotides modulate calcium levels to finely regulate NSC and GBM behavior. Calcium-associated proteins and ion channels like calcium release-activated (CRAC) channels and voltage-gated calcium channels play key roles in NSC proliferation and differentiation. Despite calcium's versatile and widespread role as a second messenger critical for regulating various cellular functions, the specific roles of calcium in stem cell niches, stem cell maintenance, and glioblastoma stem cells are still in early stages of exploration. This article aimed to provide a comprehensive and current understanding of the roles of calcium signaling in NSC behavior and interactions within their niche, which are critical for neurogenesis, brain repair mechanisms, and understanding age-related decline in stem cell function. Investigating the heterogeneity of GBM tumors resembling neurospheres and their similarity to neural stem cells (NSCs) highlights the critical involvement of calcium in governing cellular behaviors such as quiescence, proliferation, and migration. Furthermore, this manuscript illuminates various potential interventions targeting calcium channels and associated signaling pathways to mitigate GSC activities and hinder GBM recurrence, offering a promising avenue for developing novel therapeutic strategies against GBM.

Keywords

• calcium signaling
• neural stem cells
• proliferation
• glioblastoma multiforme
• glioma stem cells
• growth and progression
• aging
• cellular function and dynamics