From Local to Global Modeling for Characterizing Calcium Dynamics and Their Effects on Electrical Activity and...

Electrical activity in neurons and other excitable cells is a result of complex interactions between the system of ion channels, involving both global coupling (e.g., via voltage or bulk cytosolic Ca²⁺ concentration) of the channels, and local coupling in ion channel complexes (e.g., via local Ca²⁺ concentration surrounding Ca²⁺ channels (CaVs), the so-called Ca²⁺ nanodomains). We recently devised a model of large-conductance BK_Ca potassium currents, and hence BK_Ca-CaV complexes controlled locally by CaVs via Ca²⁺ nanodomains. We showed how different CaV types and BK_Ca-CaV stoichiometries affect whole-cell electrical behavior. Ca²⁺ nanodomains are also important for triggering exocytosis of hormone-containing granules, and in this regard, we implemented a strategy to characterize the local interactions between granules and CaVs. In this study, we coupled electrical and exocytosis models respecting the local effects via Ca²⁺ nanodomains. By simulating scenarios with BK_Ca-CaV complexes with different stoichiometries in pituitary cells, we achieved two main electrophysiological responses (continuous spiking or bursting) and investigated their effects on the downstream exocytosis process. By varying the number and distance of CaVs coupled with the granules, we found that bursting promotes exocytosis with faster rates than spiking. However, by normalizing to Ca²⁺ influx, we found that bursting is only slightly more efficient than spiking when CaVs are far away from granules, whereas no difference in efficiency between bursting and spiking is observed with close granule-CaV coupling.