CaSR Regulates Nerve Terminals Figure 7. The [Ca2+]o-modulated NSCC current in rat nerve terminals was unaffected by glutamate and GABA. A, currents activated by step depolarizations (240 to 110 mV relative to membrane potential) across a range of bath [Ca2+] (60 mM-6 mM, black traces) superimposed with those recorded during addition of 100 mM glutamate to the perfusate (red traces). Each trace represents an average of 10–20 currents at steady state solution conditions from the same cell-attached recording from a synaptosome. B, timecourse of NSCC current amplitude activated by the 200 ms voltage step every 5 seconds at three [Ca2+]o (upper trace). Same recording as A. Glutamate application is denoted by horizontal bar. C, normalized concentration-effect relationship for changes in [Ca2+]o from NSCC synaptosome recordings is unaffected by glutamate (n = 6). Currents represent NSCC current amplitude at end of voltage step relative to current before step divided by NSCC current amplitude with 60 mM Ca2+ in bath. D, currents activated by step depolarizations over a range of bath [Ca2+] (60 mM-6 mM, black traces) superimposed with those recorded during perfusion of 100 mM GABA (red traces). Each trace represents an average of 10–20 currents at steady state solution conditions from the same cell-attached recording from a synaptosome. E, timecourse of NSCC current amplitude from D at three [Ca2+]o (upper trace). GABA application is denoted by horizontal bar. E, normalized concentration-effect relationship for [Ca2+] o and NSCC amplitude in synaptosome recordings is unaffected by GABA (n = 3). Currents represent NSCC current amplitude at end of voltage step relative to current before step divided by NSCC current amplitude with 60 mM Ca2+ in bath. doi:10.1371/journal.pone.0008563.g007 to [Ca2+]o [8,44] following its entry via VACC [45,46]. A pathway that detects such falls in [Ca2+]o and indirectly activates a voltage- dependent NSCC was identified in nerve terminals in the neocortex [6]. Here we described experiments that identify CaSR as the [Ca2+]o-sensor in the [Ca2+]o-sensor-NSCC signaling pathway in neocortical terminals. Consequently presynaptic CaSR is positioned to alter presynaptic excitability and attenuate the impact of falls in [Ca2+]o on synaptic transmission [28]. In addition, our experiments led us to two further unexpected conclusions. First, direct and allosteric CaSR agonists have distinct kinetics of action. Second, glutamate and GABA do not modulate the sensitivity of the nerve terminals to changes in [Ca2+]o PLoS ONE | www.plosone.org 7 January 2010 | Volume 5 | Issue 1 | e8563