Endoplasmic Reticulum Calcium Signaling in Hippocampal Neurons

Abstract

The endoplasmic reticulum (ER) is a key organelle in cellular homeostasis, regulating calcium levels and coordinating protein synthesis and folding. In neurons, the ER forms interconnected sheets and tubules that facilitate the propagation of calcium-based signals. Calcium plays a central role in the modulation and regulation of numerous functions in excitable cells. It is a versatile signaling molecule that influences neurotransmitter release, muscle contraction, gene expression, and cell survival. This review focuses on the intricate dynamics of calcium signaling in hippocampal neurons, with particular emphasis on the activation of voltage-gated and ionotropic glutamate receptors in the plasma membrane and ryanodine and inositol 1,4,5-trisphosphate receptors in the ER. These channels and receptors are involved in the generation and transmission of electrical signals and the modulation of calcium concentrations within the neuronal network. By analyzing calcium fluctuations in neurons and the associated calcium handling mechanisms at the ER, mitochondria, endo-lysosome and cytosol, we can gain a deeper understanding of the mechanistic pathways underlying neuronal interactions and information transfer.

Keywords: calcium signaling; endoplasmic reticulum; inositol 1,4,5-trisphosphate receptor; neurons; ryanodine receptor.

Figure 1

Key channels and receptors involved in Ca²⁺ signaling in hippocampal neurons. The plasma membrane contains voltage-gated Ca²⁺ calcium channels (VGCC) and ionotropic glutamate receptors (N-methyl-D-aspartate, NMDA, or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA receptors), and loss of Ca²⁺ from the ER also activates STIM1, which then binds to Orai1 at ER-PM junctions to initiate store-operated Ca²⁺ entry (SOCE), which allow Ca²⁺ entry into neuronal cells. The plasma membrane Na⁺/Ca²⁺ exchanger (NCX) and Ca²⁺ ATPase (PMCA) regulate the free calcium concentration inside the neurons. The Ca²⁺ signal is amplified by Ca²⁺ release from the endoplasmic reticulum (ER) via ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP₃Rs) or removal by sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA). In addition, calcium buffers and mitochondria are involved in signal filtering. Mitochondria include NCX, calcium uniporter, and permeability transition pore (PTP) involved in mitochondrial calcium signaling. Nicotinic acid adenine dinucleotide phosphate (NAADP) is produced in response to agonist stimulation that activates Ca²⁺ release from endo-lysosomes.

Figure 2

Schematic representation of a pyramidal neuron. Endoplasmic reticulum network through the entire neuron at the axon, soma, dendritic tree, and spines. Focused ion beam–scanning electron microscopy revealed numerous ER-PM contacts in the cell body, with fewer links in dendrites, axons, and spines (see [20] for details). Insets from the top right represent changes in calcium concentration under train pulse electrical stimulation obtained in different regions (dendritic tree, pre-membrane, inside out of the membrane, and nuclear) of hippocampal pyramidal neuron (modified from [14]).