Precision of intracellular calcium spike timing in primary rat hepatocytes

Abstract

Extracellular stimuli are often encoded in the frequency, amplitude and duration of spikes in the intracellular concentration of calcium ([Ca2+]i). However, the timing of individual [Ca2+]i-spikes in relation to the dynamics of an extracellular stimulus is still an open question. To address this question, we use a systems biology approach combining experimental and theoretical methods. Using computer simulations, we predict that more naturalistic pulsed stimuli generate precisely-timed [Ca2+]i-spikes in contrast to the application of constant stimuli of the same dose. These computational results are confirmed experimentally in single primary rat hepatocytes upon alpha1-adrenergic stimulation. Hormonal signalling in analogy to neuronal signalling thus has the potential to make use of temporal coding on the level of single cells. The [Ca2+]i-signalling cascade provides a first example for increasing the information capacity of an intracellular regulatory signal beyond the known coding mechanisms of amplitude (AM) and frequency modulation (FM).

Microfluidic interrogation and mathematical modeling of multi-regime calcium signaling dynamics

“…4). Importantly, the new model retained oscillatory regime responses observed in previous experiments (12, 17, 24, 25) (Fig. 4a,d).…”

Prevalence of stochasticity in experimentally observed responses of pancreatic acinar cells to acetylcholine

“…The reported results are fully in agree-ment with the previous analysis of experimental data and theoretical predictions. [24][25][26] Combined with previous results, they represent an important experimentally based confirmation of previous theoretical declarations, [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] which hypothesized that stochasticity must be taken into account when processes at the cellular level are modeled. Moreover, the unquestionable existence of inherent fluctuations confirms the feasibility of noise-induced phenomena at the single cell scale, such as stochastic or coherence resonance, which were frequently observed and studied theoretically.…”

Stochastic Aspects of Oscillatory Ca2+ Dynamics in Hepatocytes

“…Of particular interest is the conclusion reached by these authors that fluctuations in intracellular InsP 3 and Ca 21 levels decrease the threshold level of gap junction permeability necessary to coordinate Ca 21 spiking between adjacent cells. In vivo, an additional level of complexity arises from the fact that the hormonal stimulus does not remain strictly constant and, in some instances, even follows an oscillatory pattern (11,54). Thus, as is nowadays largely emphasized for genetic systems (28,55), molecular noise appears to be an important component of the oscillatory Ca 21 dynamics, which has to be considered for a detailed elucidation of this widespread signaling pathway.…”