Calcium microdomains in regulated exocytosis

Katz and co-workers showed that Ca2+ triggers exocytosis. The existence of sub-micrometer domains of greater than 100 μM [Ca2+]i was postulated on theoretical grounds. Using a modified, low-affinity aequorin, Llinas et al. were the first to demonstrate the existence of Ca2+ ‘microdomains’ in squid presynaptic terminals. Over the past several years, it has become clear that individual Ca2+ nano- and microdomains forming around the mouth of voltage-gated Ca2+ channels ascertain the tight coupling of fast synaptic vesicle release to membrane depolarization by action potentials. Recent work has established different geometric arrangements of vesicles and Ca2+ channels at different central synapses and pointed out the role of Ca2+ syntillas – localized, store operated Ca2+ signals – in facilitation and spontaneous release. The coupling between Ca2+ increase and evoked exocytosis is more sluggish in peripheral terminals and neuroendocrine cells, where channels are less clustered and Ca2+ comes from different sources, including Ca2+ influx via the plasma membrane and the mobilization of Ca2+ from intracellular stores. Finally, also non- (electrically) excitable cells display highly localized Ca2+ signaling domains. We discuss in particular the organization of structural microdomains of Bergmann glia, specialized astrocytes of the cerebellum that have only recently been considered as secretory cells. Glial microdomains are the spatial substrate for functionally segregated Ca2+ signals upon metabotropic activation. Our review emphasizes the large diversity of different geometric arrangements of vesicles and Ca2+ sources, leading to a wide spectrum of Ca2+ signals triggering release.