Fundamentals of Cellular Calcium Signaling: A Primer

Abstract

Ionized calcium (Ca²⁺) is the most versatile cellular messenger. All cells use Ca²⁺ signals to regulate their activities in response to extrinsic and intrinsic stimuli. Alterations in cellular Ca²⁺ signaling and/or Ca²⁺ homeostasis can subvert physiological processes into driving pathological outcomes. Imaging of living cells over the past decades has demonstrated that Ca²⁺ signals encode information in their frequency, kinetics, amplitude, and spatial extent. These parameters alter depending on the type and intensity of stimulation, and cellular context. Moreover, it is evident that different cell types produce widely varying Ca²⁺ signals, with properties that suit their physiological functions. This primer discusses basic principles and mechanisms underlying cellular Ca²⁺ signaling and Ca²⁺ homeostasis. Consequently, we have cited some historical articles in addition to more recent findings. A brief summary of the core features of cellular Ca²⁺ signaling is provided, with particular focus on Ca²⁺ stores and Ca²⁺ transport across cellular membranes, as well as mechanisms by which Ca²⁺ signals activate downstream effector systems.

Figure 1.

Cytosolic Ca²⁺ signals arise via Ca²⁺ release from intracellular organelles and/or Ca²⁺ influx across the plasma membrane. During physiological Ca²⁺ signaling, the averaged cytosolic Ca²⁺ concentration typically increases from ∼100 nm to ∼1 µm, depending on the stimulus and factors such as buffering of Ca²⁺ by mitochondria and Ca²⁺-binding proteins. Cellular processes are specifically switched on or off when the cytosolic Ca²⁺ concentration is altered. The main intracellular Ca²⁺ store is the endoplasmic reticulum (ER), but also the nuclear envelope, Golgi, and acidic compartments such as lysosomes function as Ca²⁺ stores (see text).

Figure 2.

Ca²⁺-sequestering organelles. Cellular Ca²⁺ signaling involves combinations of organelles depending on the tissue type and stimulus. Although there is considerable overlap in some of the organelles’ characteristics, they also have discrete properties that imbue each of the organelles with the ability to generate distinctive Ca²⁺ signals. Mitochondria and peroxisomes are not constitutive Ca²⁺ stores, but have the capacity to sequester Ca²⁺ during cytosolic Ca²⁺ increases. For more details, see Wang et al. (2019), Chen et al. (2019), Lloyd-Evans and Waller-Evans (2019), Wacquier et al. (2019), and Vangeel and Voets (2019). A significant Ca²⁺ store not shown in the figures is the sarcoplasmic reticulum (SR), which plays a critical Ca²⁺ signaling role in muscle cells. For details about SR function and Ca²⁺ homeostasis see Wang et al. (2019) and Gilbert et al. (2019). SERCA, sarcoendoplasmic reticulum Ca²⁺-ATPase; SPCA, Golgi/secretory pathway Ca²⁺ ATPase; TPC, two-pore channel; IP₃R, inositol 1,4,5-trisphosphate receptor; RyR, ryanodine receptor.

Figure 3.

IP₃-mediated Ca²⁺ release is a common outcome from a number of cellular signaling processes and evokes a range of downstream outcomes. A generic pathway leading from hormone-receptor activation, activation of a heterotrimeric G-protein (Gq) and phospholipase C β (PLC-β) is depicted centrally. However, the other PLC isoforms provide alternative mechanisms for activating Ca²⁺ signaling via IP₃Rs. (From Bootman et al. 2009; adapted, with permission, from Company of Biologists © 2009.)

Figure 4.

Generation of Ca²⁺ oscillations via positive and negative feedback on IP₃Rs. The sequence of cartoons 1–5 depict the status of cytosolic Ca²⁺, IP₃R activity, and Ca²⁺ store content during the various phases of a Ca²⁺ oscillation. Phase 1 represents the cell at rest, before application of an extracellular stimulus. Phase 2 shows the cell subsequent to agonist–receptor interaction, when there is IP₃ production but no Ca²⁺ release via IP₃Rs. Phase 3 indicates the initial opening of IP₃Rs and an increasing cytosolic Ca²⁺ concentration, which exerts a positive (+Ve) feedback on the IP₃R, thereby promoting further Ca²⁺ release. At phase 4, the cytosolic Ca²⁺ concentration has increased to the point where it inhibits IP₃R activity via negative (−Ve) feedback and hence Ca²⁺ release terminates. At this point, the Ca²⁺ store is depleted and Ca²⁺ influx is activated. Phase 5 indicates the recovery of the cell as Ca²⁺ is transported from the cytosol toward the intracellular stores and the extracellular environment and the negative feedback from cytosolic Ca²⁺ is relaxed.

Figure 5.

Examples of Ca²⁺ signaling via membrane contact sites. (A)–(D) Well-known situations where the close apposition of membranes/organelles is essential for initiation or communication of Ca²⁺ signals. VOCC, voltage-operated Ca²⁺ channel; SL, sarcolemma; VDAC, voltage-dependent anion channel; MCU, mitochondrial Ca²⁺ uniporter; TPC, two-pore channel; TRPML, mucolipin subfamily of transient receptor potential channels; CICR, Ca²⁺-induced Ca²⁺ release; R/I, ryanodine receptor or IP₃ receptor.