Presynaptic roles of intracellular Ca(2+) stores in signalling and exocytosis

The signalling roles of Ca(2+)(ic) (intracellular Ca(2+)) stores are well established in non-neuronal and neuronal cells. In neurons, although Ca(2+)(ic) stores have been assigned a pivotal role in postsynaptic responses to G(q)-coupled receptors, or secondarily to extracellular Ca(2+) influx, the functions of dynamic Ca(2+)(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 Ca(2+)(ic) in presynaptic function, and discuss loci at which this source of Ca(2+) may impinge. Nerve terminal preparations provide good models for functionally examining putative Ca(2+)(ic) stores under physiological and pathophysiological stimulation paradigms, using Ca(2+)-dependent activation of resident protein kinases as sensors for fine changes in intracellular Ca(2+) levels. We conclude that intraterminal Ca(2+)(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 Ca(2+)(ic) store activation may thereby contribute to excitotoxicity and eventual synaptopathy.