Topic Introduction Translating Intracellular Calcium Signaling into Models Rüdiger Thul 1 School of Mathematical Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom The rich experimental data on intracellular calcium has put theoreticians in an ideal position to derive models of intracellular calcium signaling. Over the last 25 years, a large number of modeling frameworks have been suggested. Here, I will review some of the milestones of intracellular calcium modeling with a special emphasis on calcium-induced calcium release (CICR) through inositol-1,4,5-trisphosphate and ryanodine receptors. I will highlight key features of CICR and how they are represented in models as well as the challenges that theoreticians face when translating our current understanding of calcium signals into equations. The selected examples demonstrate that a successful model provides mechanistic insights into the molecular machinery of the Ca 2+ signaling toolbox and determines the contribution of local Ca 2+ release to global Ca 2+ patterns, which at the moment cannot be resolved experimentally. INTRODUCTION One of the most fascinating features of calcium (Ca 2+ ) as a second messenger is its versatility (Berridge et al. 2000). Almost every cell type shows Ca 2+ signals, and even within a single cell the number of signaling pathways that involve Ca 2+ is huge. From a modeler’s perspective the broad spectrum of interactions renders Ca 2+ an intriguing yet challenging study object. The fascination originates from the large dynamic repertoire of Ca 2+ signals. Most Ca 2+ responses begin with the elevation of the cytosolic Ca 2+ concentration through either Ca 2+ entry from the extracellular space or Ca 2+ liberation from intracellular organelles such as the endoplasmic or sarcoplasmic reticulum (ER/SR). Although the molecular details of the ion channels that are responsible for the increase in the cytosolic Ca 2+ concentration differ, in all cases, Ca 2+ forms a plume of high concentration around the site of influx just after a channel opens. These microdomains form the smallest functional unit of intracellular Ca 2+ signals (Berridge 2006) from which larger Ca 2+ patterns are formed. For example, it is the orchestrated action of microdomains that gives rise to cellular responses such as Ca 2+ waves and Ca 2+ oscillations (Bootman et al. 1997). Some Ca 2+ waves travel through the entire cell, while others only spread through parts of the cytoplasm resulting in abortive waves. The existence of Ca 2+ microdomains and Ca 2+ waves already points to a defining characteristic of intracellular Ca 2+ signals—they vary largely in their temporal duration and their spatial spread. On the temporal scale, intracellular Ca 2+ signals range from events faster than microseconds (binding and unbinding of Ca 2+ to target mole- cules) to cellular Ca 2+ transients that last minutes (Ca 2+ waves and oscillations). At the same time, intracellular Ca 2+ operates on length scales from a few nanometers (molecular binding sites) up to hundreds of micrometers (Ca 2+ waves). The challenge for modelers arises from the realization that a complete account of intracellular Ca 2+ requires us to incorporate the entire spatiotemporal spread, that is, more than eight orders of magnitude in space and more than six orders of magnitude in time. 1 Correspondence: ruediger.thul@nottingham.ac.uk © 2014 Cold Spring Harbor Laboratory Press Cite this introduction as Cold Spring Harb Protoc; doi:10.1101/pdb.top066266 463 Cold Spring Harbor Laboratory Press on November 8, 2016 - Published by http://cshprotocols.cshlp.org/ Downloaded from