Calcium and Neural Stem Cell Proliferation

Abstract

Intracellular calcium plays a pivotal role in central nervous system (CNS) development by regulating various processes such as cell proliferation, migration, differentiation, and maturation. However, understanding the involvement of calcium (Ca²⁺) in these processes during CNS development is challenging due to the dynamic nature of this cation and the evolving cell populations during development. While Ca²⁺ transient patterns have been observed in specific cell processes and molecules responsible for Ca²⁺ homeostasis have been identified in excitable and non-excitable cells, further research into Ca²⁺ dynamics and the underlying mechanisms in neural stem cells (NSCs) is required. This review focuses on molecules involved in Ca²⁺ entrance expressed in NSCs in vivo and in vitro, which are crucial for Ca²⁺ dynamics and signaling. It also discusses how these molecules might play a key role in balancing cell proliferation for self-renewal or promoting differentiation. These processes are finely regulated in a time-dependent manner throughout brain development, influenced by extrinsic and intrinsic factors that directly or indirectly modulate Ca²⁺ dynamics. Furthermore, this review addresses the potential implications of understanding Ca²⁺ dynamics in NSCs for treating neurological disorders. Despite significant progress in this field, unraveling the elements contributing to Ca²⁺ intracellular dynamics in cell proliferation remains a challenging puzzle that requires further investigation.

Keywords: calcium signaling; differentiation; neural stem/progenitor cells; proliferation; radial glial cells.

Figure 7

Radial glia cell cycle and conexin-43. (A) Scheme showing the level of expression of Cx43 during the cell cycle and gap junction. During the S Phase, Cx43 is highly expressed, and RGCs are coupled; as the cell cycle progresses, Cx43 decreases its expression, and RGCs are less coupled, while in the M phase, cells are uncoupled. (B) In the S phase, radial glia initiates Ca²⁺ waves by releasing ATP, which binds to P2Y1 receptors in the membrane of adjacent cells, inducing IP3 Ca²⁺ release from the endoplasmic reticulum (ER). Created using BioRender.com based on [23,242,252].

Figure 1

Scheme of the cellular phenotype generated during development from a heterogeneous population of neural stem cells. NSCs proliferate symmetrically () to increase their pool or asymmetrically (black) to give rise, directly or indirectly, in a time-dependent manner, to neurons (green arrows), astrocytes (blue arrows), and oligodendrocytes (red arrow). NSCs = neural stem cells; IPCs = intermediate progenitor cells. Blue doted arrow = repressed gliogenic signals; Blunt green arrow = pro-neuronal genes repressing gliogenic signals; Blunt blue arrow = gliogenic signals repressing neuronal genes. Created using BioRender.com.

Figure 2

Calcium entry stimulated via GPCR activation in neural stem cells. G_αqPCR is activated through ligand binding promoting PLC activation, Ca²⁺ is released from the endoplasmic reticulum (ER), Ca²⁺ depletion in the ER is sensed by the stromal interaction molecules (STIM) and its conformational change to move and contact Ca²⁺ channels (ORAI and TRPC1) in the cell membrane to promote Ca²⁺ entrance for ER refill through sarcoendoplasmic reticulum Ca²⁺ ATPase (SERCA) and bind to proteins with roles in cell proliferation. Created using BioRender.com.

Figure 3

TRPCs in neural stem cells. Scheme showing the two pathways for TRPCs activation: the store-operated (light green arrows) and receptor-operated activation (purple arrows) pathways. Black arrows = agonist GPCR pathways involving G_αq/11 and downstream signaling pathway for Ca²⁺ ER release; green arrows in the middle of TRPCs and IP₃R = extracellular/intracellular Ca²⁺ entrance and release from de ER, respectively. And, Blunt brown arrow = negative regulation of CaM on TRPCs. Created using BioRender.com.

Figure 4

TRPVs and neural stem cell proliferation. The Scheme shows the TRPVs’ activation signals and related pathways for neural stem cell proliferation. Purple arrow = PI3K participation in TRPV cell membrane localization. Once in the membrane (black arrow in the left) TRPVs can be activated promoting Ca²⁺ entrance (green arrows). TRPV3 and 4 are negatively regulated by CaM (blunt brown arrow) and can be activated by PKC (blue arrow) through GPCR DAG and Ca²⁺ release (black arrows in the right). Yellow arrow = extracellular Ca²⁺ influence TRPV4 activity. Created using BioRender.com.

Figure 5

TRPPs. Scheme showing the interaction of PC2 with other channels and receptors in the plasma membrane and the endoplasmic reticulum membrane (ER). Created using BioRender.com.

Figure 6

RTK pathways. Scheme showing the pathways activated by RTKs. The pathways in the black arrows are the PLCγs and the cross-taking with GPCR receptors, both promoting an increase in [Ca²⁺]_i. Created using BioRender.com.