Neuronal Calcium Sensor 1 and Activity-Dependent Facilitation of P/Q-Type Calcium Currents at Presynaptic Nerve Terminals

Abstract

P/Q-type presynaptic calcium currents (IpCa) undergo activity-dependent facilitation during repetitive activation at the calyx of the Held synapse. We investigated whether neuronal calcium sensor 1 (NCS-1) may underlie this phenomenon. Direct loading of NCS-1 into the nerve terminal mimicked activity-dependent IpCa facilitation by accelerating the activation time of IpCa in a Ca2+-dependent manner. A presynaptically loaded carboxyl-terminal peptide of NCS-1 abolished IpCa facilitation. These results suggest that residual Ca2+ activates endogenous NCS-1, thereby facilitating IpCa. Because both P/Q-type Ca2+ channels and NCS-1 are widely expressed in mammalian nerve terminals, NCS-1 may contribute to the activity-dependent synaptic facilitation at many synapses.

Down-regulation of Voltage-gated Ca2+ Channels by Neuronal Calcium Sensor-1 Is β Subunit-specific

“…In these cell types, NCS-1 modulates synaptic transmission (14,22,34), secretion (21,25), or cellular excitability (18,20) via complex processes that include regulation of key enzymes for membrane transport (15,17,23,24,35) and specific regulation of various ion channels (16, 18 -20, 28). K ϩ channels were the first ion channel target to be characterized in expression systems (26,36).…”

“…The fact that the decrease in current amplitude and the modifications in the channel properties did not have the same ␤ subunit specificity suggested different underlying mechanisms. Direct interactions between Ca 2ϩ channels and NCS-1 at the plasma membrane have not been reported so far, but the presence of NCS-1 in synaptic-like microvesicles and its colocalization in presynaptic terminals with the proteins of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex, VAMP (45) and syntaxin (18), also known to interact with P/Q Ca 2ϩ channels (1), suggest that NCS-1 is appropriately located for these potential functional interactions. Indeed, a previously published work (18) reported an enhancement of the facilitation of the P/Q-type Ca 2ϩ channel in the Calyx of Held, occurring via an acceleration of current activation.…”

“…Direct interactions between Ca 2ϩ channels and NCS-1 at the plasma membrane have not been reported so far, but the presence of NCS-1 in synaptic-like microvesicles and its colocalization in presynaptic terminals with the proteins of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex, VAMP (45) and syntaxin (18), also known to interact with P/Q Ca 2ϩ channels (1), suggest that NCS-1 is appropriately located for these potential functional interactions. Indeed, a previously published work (18) reported an enhancement of the facilitation of the P/Q-type Ca 2ϩ channel in the Calyx of Held, occurring via an acceleration of current activation. A similar frequency-dependent facilitation was also apparent in oocytes (data not shown), but the large membrane capacitance of the oocytes did not allow a precise analysis of the modifications in the activation kinetics.…”

“…Overexpression of a dominant-negative mutant of NCS-1, which displays impaired Ca 2ϩ -dependent conformational changes (19), or direct loading of presynaptic nerve terminals with NCS-1 suggested that voltage-independent inhibition, as well as activity-dependent facilitation of P/Q-type Ca 2ϩ channels (Ca V 2.1), could be controlled by NCS-1, possibly via direct protein-protein interactions (18). Effects on N-type Ca 2ϩ channel (Ca V 2.2) properties have also been reported (20), and the expression of NCS-1 in mammalian cardiac myocytes and subsequent effect on K ϩ channel expression (26) gave rise to the possibility that NCS-1 may regulate multiple types of Ca 2ϩ channels and other voltage-dependent ion channels, not only in neurons (27).…”

The Diversity of Calcium Sensor Proteins in the Regulation of Neuronal Function

“…3) appear to be specific for NCS-1 (Haynes et al 2006). Various studies have implicated NCS-1 in the regulation of VGCCs (Weiss et al 2000;Tsujimoto et al 2002;Dason et al 2009) but there is as yet no evidence for a direct interaction. Interestingly, in Drosophila, the effects of NCS-1 on both neurotransmission and nerve-terminal growth can be explained by a functional interaction with the VGCC cacophony, which is related to the mammalian P/Q-type VGCCs (Dason et al 2009).…”