Timing in cellular Ca2+ signaling

Abstract

Calcium (Ca2+) signals are generated across a broad time range. Kinetic considerations impact how information is processed to encode and decode Ca2+ signals, the choreography of responses that ensure specific and efficient signaling and the overall temporal amplification such that ephemeral Ca2+ signals have lasting physiological value. The reciprocal importance of timing for Ca2+ signaling, and Ca2+ signaling for timing is exemplified by the altered kinetic profiles of Ca2+ signals in certain diseases and the likely role of basal Ca2+ fluctuations in the perception of time itself.

Figure 1. Kinetic orchestration of Ca²⁺ signals

Schematic overview of the impact of timing in cellular Ca²⁺ signaling. Aspects of timing impact how extracellular signals are interpreted and choreographed into specific profiles of cytoplasmic [Ca²⁺] signals (‘encoding’). Different Ca²⁺ signals result depending on how cells interpret dynamic environmental cues (‘integrating inputs’, triangles) to contextualize and temporally order specific signaling processes (‘choreographing responses’). Temporal aspects of the resultant cytoplasmic Ca²⁺ signal – notably, variability in duration (top) and periodicity (lower) – are sensed by subsets of Ca²⁺-sensitive effectors via Ca²⁺-binding sites of varied affinity, kinetics and interdependence, resulting in their selective activation (‘decoding: targeting effectors’) to yield discrete responses (stars).

Figure 2. Temporal integration empowers diverse outcomes from limited inputs

Principles of timing impacting signal interpretation for single and multiple (dual) inputs. (a) ‘Context’ determines whether a single (‘1’) signal will be effective at evoking a response (▲ → no response/response). Bottom, Two inputs associated with specific individual responses can produce several different responses (right) when (b) the duration of their effects compound (‘summation’), (c) the order of their presentation matters (‘sequentiality’; ▲△→response ‘x’, △▲→ response ‘y’), (d) the relative timing, but not necessarily order, of the arrival of each input is critical (‘coincidence detection’, ▲...△/△...▲→ response ‘x’, △▲ or ▲△→ response ‘y’) or (e) an example of ‘associative’ memory where specific combinations of presented signals (e.g. one of two signals ▲ and △ presented ‘n’ times) can trigger a number of unique (≤2ⁿ) responses. Strategies for temporal ‘memory’ of Ca²⁺ signals (e.g. priming & persistence, are discussed under ‘duration’).

Figure 3. Physiological harmonics: frequency encoding of Ca²⁺ signals

The ~10,000,000-fold range in the periodicity (Hz, left) of repetitive Ca²⁺ changes observed in different cells/tissues, using data from non-excitable cells (orange, [112,113]), muscle (purple, [73,114,115]), embryos (green, [14,116]) and neurons (blue [67,117]). Numbers represent citations to examples delimiting each range. Right (red), estimates of optimal Ca²⁺ spiking frequencies for half-maximal activation of the indicated proteins from: Ras [75], NF-kB [64], NFAT [64], CamKII [63], PKC [33]. These obviously represent single point estimates from a broader in vivo range.