Abstract
BackgroundNerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. Consequently characterization of the functional properties of ion channels at nerve terminals is crucial to understand the regulation of transmitter release. Direct recordings from small neocortical nerve terminals have revealed that external [Ca2+] ([Ca2+]o) indirectly regulates a non-selective cation channel (NSCC) in neocortical nerve terminals via an unknown [Ca2+]o sensor. Here, we identify the first component in a presynaptic calcium signaling pathway.Methodology/Principal FindingsBy combining genetic and pharmacological approaches with direct patch-clamp recordings from small acutely isolated neocortical nerve terminals we identify the extracellular calcium sensor. Our results show that the calcium-sensing receptor (CaSR), a previously identified G-protein coupled receptor that is the mainstay in serum calcium homeostasis, is the extracellular calcium sensor in these acutely dissociated nerve terminals. The NSCC currents from reduced function mutant CaSR mice were less sensitive to changes in [Ca2+]o than wild-type. Calindol, an allosteric CaSR agonist, reduced NSCC currents in direct terminal recordings in a dose-dependent and reversible manner. In contrast, glutamate and GABA did not affect the NSCC currents.Conclusions/SignificanceOur experiments identify CaSR as the first component in the [Ca2+]o sensor-NSCC signaling pathway in neocortical terminals. Decreases in [Ca2+]o will depress synaptic transmission because of the exquisite sensitivity of transmitter release to [Ca2+]o following its entry via voltage-activated Ca2+ channels. CaSR may detects such falls in [Ca2+]o and increase action potential duration by increasing NSCC activity, thereby attenuating the impact of decreases in [Ca2+]o on release probability. CaSR is positioned to detect the dynamic changes of [Ca2+]o and provide presynaptic feedback that will alter brain excitability.
Highlights
Neurotransmitter release from nerve terminals underlies synaptic communication in the brain
The concentration-effect relationship for the normalized non-selective cation channel (NSCC) current amplitudes (Figure 1D) confirmed that calcium-sensing receptor (CaSR)+/2 terminals had a lower affinity than the CaSR+/+ terminals (IC50 1.660.2 mM versus 1.160.07 mM respectively; ANOVA, p = 0.032)
We measured the NSCC current amplitudes elicited by 6 mM and 60 mM bath Ca2+ to test if the maximum and minimum currents respectively were dependent on genotype
Summary
Neurotransmitter release from nerve terminals underlies synaptic communication in the brain. Invasion of the nerve terminal by an axonal spike activates voltage-gated channels, triggering calcium entry and exocytosis of transmitter-containing vesicles [1]. Release probability at a given synapse is dynamic; the ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry [2,3,4]. Characterization of the functional properties of ion channels at nerve terminals is crucial to understand presynaptic regulation of transmitter release. Nerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. We identify the first component in a presynaptic calcium signaling pathway
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