Function Suggests Nano-Structure: Quantitative Structural Support for SNARE-Mediated Pore Formation

Granule secretory content is released in either basal or calcium-activated complete exocytosis mode. A vital element in these processes is the establishment of a fusion pore between the granule membrane and the plasma membrane, initiated by the formation of a circular rosette docking arrangement of SNARE protein complexes. The controversially disputed number of SNARE complexes needed for granule priming leading to the formation of the fusion pore, is granule-size dependent and varies between secretion modes. Resorting to a statistical mechanics approach that views SNARE complexes and Ca²⁺ ions as interacting particles, we have developed a relationship that links secretion rate to SNARE rosette size, Ca²⁺ concentration and Ca²⁺ ion cooperativity. Data are presented and discussed which suggest this SNARE-dependent generalization of existing narrow-range biophysical models that correlate secretion rate with Ca²⁺ concentration and maximal Ca²⁺ ion cooperativity. Evidence from dozens of examples in the literature advocate for this relation, which holds through the entire biological range. The coalescence of so many areas of diverse research methodologies has greatly augmented our understanding of so many different sequences of granule life cycle. Accordingly, these new tools may become valuable in a variety of electrophysiological experiments.