Figure 13:

Spatial regulation of diffusible signaling molecules.

Spatial Ca²⁺ gradients are primarily shaped by 4 effects: the rate of Ca²⁺ influx into the cytosol from the extracellular environment and intracellular stores, the efflux of Ca²⁺ out of the cytosol by Ca²⁺ pumps, Ca²⁺ binding proteins which buffer the changes in the free Ca²⁺ concentration and diffusion of Ca²⁺ through the cytosol. B) While the effect of Ca²⁺ influx by a single channel may be limited by the rate of Ca²⁺ flux through the channel and the rate of diffusion (top), Ca²⁺-induced Ca²⁺ release (CICR), where an increase in Ca²⁺ can stimulate the opening of neighboring Ca²⁺ channels, creates a positive feedback loop that can create a wave of Ca²⁺ release that spreads faster than possible by diffusion alone (bottom). C) The spatial arrangement of adenylyl cyclases (ACs), which produce cAMP, and phosphodiesterases (PDEs), which degrade cAMP, regulate the formation of gradients of the diffusible messenger cAMP. For example, rat hippocampal neurons at 5 days in vitro (DIV5), when the axons have started to become more thoroughly established, have been observed to exhibit an axon-directed gradient of cAMP accumulation in response to Forskolin stimulation of ACs⁸²⁵. Conversely, at an earlier time point of 3 days in vitro (DIV3), cAMP production was observed to be much more limited in response to Forskolin, which was hypothesized to be due to negative feedback mediated by PKA and PDE, which are localized to distal regions of an axon by an A-Kinase Anchoring Protein (AKAP)⁸²⁵.