BPS2026 – News from the calcium signaling machine room—Building data-driven models of the inositol-trisphosphate receptor (IPR) from single-channel data

Intracellular calcium signals regulate a variety of life-sustaining physiological mechanisms, ranging from the heartbeat via respiration and metabolism to psychological processes. Although these signals might appear as deterministic global oscillations or waves that spread continuously from one end of the cell to the other, they are generated by the stochastic release of calcium by ion channels. Ion channels are proteins that control the calcium flux into the cytosol by opening and closing tiny pores in the membranes of intracellular stores, a process which relies on highly complex molecular dynamics of the underlying three-dimensional protein structure of the channel. Developing mathematical models of calcium dynamics from first principles requires parametrizing Markov models of calcium channels using single-channel data. Accounting for the dynamical transitions between different three-dimensional arrangements of the channel protein in these models continues to be a difficult challenge. In this talk, I will illustrate fundamental difficulties in associating states of a Markov model with conformational states of an ion channel. I will argue that it is preferable to use additional data on modal gating and the delayed response of the channel to changes in ligand concentrations for gaining more direct insight into the biophysical dynamics of the channel protein. Using the inositol-trisphosphate receptor (IPR) as an example, I will demonstrate how newly developed modular architectures enable us to parametrize a model from multiple sources of data. In the last part of the talk, this model will be used for investigating stochastic calcium release from a cluster of IPR channels.