Presynaptic roles of intracellular Ca²⁺ stores in signalling and exocytosis

The signalling roles of Ca²⁺_ic (intracellular Ca²⁺) stores are well established in non-neuronal and neuronal cells. In neurons, although Ca²⁺_ic stores have been assigned a pivotal role in postsynaptic responses to G_q-coupled receptors, or secondarily to extracellular Ca²⁺ influx, the functions of dynamic Ca²⁺_ic stores in presynaptic terminals remain to be fully elucidated. In the present paper, we review some of the recent evidence supporting an involvement of Ca²⁺_ic in presynaptic function, and discuss loci at which this source of Ca²⁺ may impinge. Nerve terminal preparations provide good models for functionally examining putative Ca²⁺_ic stores under physiological and pathophysiological stimulation paradigms, using Ca²⁺-dependent activation of resident protein kinases as sensors for fine changes in intracellular Ca²⁺ levels. We conclude that intraterminal Ca²⁺_ic stores may, directly or indirectly, enhance neurotransmitter release following nerve terminal depolarization and/or G-protein-coupled receptor activation. During conditions that prevail following neuronal ischaemia, increased glutamate release instigated by Ca²⁺_ic store activation may thereby contribute to excitotoxicity and eventual synaptopathy.