Abstract
AimNeurotransmitter release is elicited by an elevation of intracellular Ca2+ concentration ([Ca2+]i). The action potential triggers Ca2+ influx through Ca2+ channels which causes local changes of [Ca2+]i for vesicle release. However, any direct role of extracellular Ca2+ (besides Ca2+ influx) on Ca2+-dependent exocytosis remains elusive. Here we set out to investigate this possibility on rat dorsal root ganglion (DRG) neurons and chromaffin cells, widely used models for studying vesicle exocytosis.ResultsUsing photolysis of caged Ca2+ and caffeine-induced release of stored Ca2+, we found that extracellular Ca2+ inhibited exocytosis following moderate [Ca2+]i rises (2–3 µM). The IC50 for extracellular Ca2+ inhibition of exocytosis (ECIE) was 1.38 mM and a physiological reduction (∼30%) of extracellular Ca2+ concentration ([Ca2+]o) significantly increased the evoked exocytosis. At the single vesicle level, quantal size and release frequency were also altered by physiological [Ca2+]o. The calcimimetics Mg2+, Cd2+, G418, and neomycin all inhibited exocytosis. The extracellular Ca2+-sensing receptor (CaSR) was not involved because specific drugs and knockdown of CaSR in DRG neurons did not affect ECIE.Conclusion/SignificanceAs an extension of the classic Ca2+ hypothesis of synaptic release, physiological levels of extracellular Ca2+ play dual roles in evoked exocytosis by providing a source of Ca2+ influx, and by directly regulating quantal size and release probability in neuronal cells.
Highlights
Neurotransmitter and hormone secretion are precisely controlled in neurons and endocrine cells where Ca2+ plays a pivotal role [1,2,3]
There are two kinds of depolarization-induced exocytosis in the somata of dorsal root ganglion (DRG) neurons [16,30]; in the present study, we focused on the Ca2+-dependent exocytosis by holding the soma at resting potential [13,16,30]
Exocytosis at both 0 and 2.5 mM [Ca2+]o was facilitated by cAMP elevation with forskolin, presumably via activation of protein kinase A (PKA), which is a well-known feature of Ca2+
Summary
Neurotransmitter and hormone secretion are precisely controlled in neurons and endocrine cells where Ca2+ plays a pivotal role [1,2,3]. The rapid influx of Ca2+ through presynaptic Ca2+ channels and postsynaptic Ca2+-permeable channels leads to a reduction of extracellular Ca2+ concentration ([Ca2+]o) given the limited Ca2+ storage capacity within the synaptic cleft [4,5]. It is known that extracellular Ca2+ modulates ion channels in neurons; for example, lowering [Ca2+]o shifts the voltage dependence of sodium channels to more negative potentials, via a biophysical surface charge effect [7]. In addition to this biophysical effect, [Ca2+]o may have a biochemical effect on cell function by regulating non-selective cation channels and TRPM7 channel [8,9,10,11]
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