Figure 1. Neuronal calcium signaling.

Schematic representation of neuronal Ca²⁺ signaling. Main Ca²⁺ influx sources in plasma membrane (PM) are voltage-gated (VGCC), the ligand–operated (ROC) and the store-operated (SOCE) Ca²⁺ channels. Plasma membrane Ca²⁺ ATPase (PMCA) and the Na⁺/Ca²⁺ exchanger (NCX) extrude Ca²⁺ from cytosol into the extracellular space. Activation of metabotropic glutamate receptors (mGluR) stimulate Ca²⁺ mobilization from endoplasmic reticulum (ER) via inositol 1,4,5 - trisphosphate receptor (IP₃R). Ca²⁺ also can be mobilized from ER via ryanodine receptors (RyR) amplifying cytoplasmic Ca²⁺ signals. Reuptake Ca²⁺ into the ER is operated by the ATPase SERCA. ER Ca²⁺ depletion is detected by Ca²⁺ sensors STIM1/2. To maintain the balance, Ca²⁺ is released from ER through passive leakage channels presenilins (PSEN1/2). The transmission of Ca²⁺-dependent signals to the nucleus occurs with the help of transcription factors cAMP response element-binding protein (CREB) and nuclear factor of activated T-cells (NFAT). The mitochondrial (mito) Ca²⁺ handling systems include mitochondrial Ca²⁺ uniporter (MCU), voltage-dependent anion channel type 1 (VDAC1), mitochondrial permeability transition pore (mPTP). Ca²⁺ concentration in cytosolic maintain with Ca²⁺-binding proteins: calbindin-28 (CaB), parvalbumin (PV) and calretinin (CaR), and inside ER with calreticulin (CRT) and calnexin (CNX). Ca²⁺-activated proteins include calmodulin (CaM), Ca²⁺/ calmodulin-dependent protein kinase type II (CAMKII) and Ca²⁺/calmodulin-dependent protein phosphatase calcineurin (CaN). Figure created with BioRender.com.