P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-1A

Abstract

Spatial and temporal changes in intracellular calcium concentrations are critical for controlling gene expression in neurons. In many neurons, activity-dependent calcium influx through L-type channels stimulates transcription that depends on the transcription factor CREB by activating a calmodulin-dependent pathway. Here we show that selective influx of calcium through P/Q-type channels is responsible for activating expression of syntaxin-1A, a presynaptic protein that mediates vesicle docking, fusion and neurotransmitter release. The initial P/Q-type calcium signal is amplified by release of calcium from intracellular stores and acts through phosphorylation that is dependent on the calmodulin-dependent kinase CaM K II/IV, protein kinase A and mitogen-activated protein kinase kinase. Initiation of syntaxin-1A expression is rapid and short-lived, with syntaxin-1A ultimately interacting with the P/Q-type calcium channel to decrease channel availability. Our results define an activity-dependent feedback pathway that may regulate synaptic efficacy and function in the nervous system.

Old proteins, developing roles: The regulation of calcium channels by synaptic proteins

“…132 The molecular mechanism of this negative feedback regulation needs to be explored further, as does a possible role of other Ca V 2 channel family members.…”

“…Temporally and spatially controlled channel splicing can dictate (1) intrinsic calcium channel biophysical properties, and (2) the selective expression and association of distinct synaptic protein isoforms that exert regulatory effects on calcium channel function. 132 Additionally, there is evidence that channel-vesicle stoichiometry changes over development, with fewer channels coupled to a single vesicle SNARE complex as the synapse matures, 133 a phenomenon that could possibly be regulated by splicing of either calcium channels or synaptic proteins.…”

Bidirectional Modulation of Transmitter Release by Calcium Channel/Syntaxin InteractionsIn Vivo

“…The decrease in transmitter release was interpreted to be attributable to dissociation of the Ca 2ϩ channel from the Ca 2ϩ sensor for transmitter release. Other experiments suggest that the interaction between syntaxin 1A and the synprint site enhances calcium channel inactivation (Bezprozvanny et al, 1995;Wiser et al, 1996;Degtiar et al, 2000;Bergsman and Tsien, 2000;Jarvis et al, 2000Jarvis et al, , 2002Smirnova et al, 1995;Sutton et al, 1999;Zhong et al, 1999;Zamponi, 2003). In particular, coexpression of syntaxin 1A with N-type Ca 2ϩ channels in Xenopus oocytes increases inactivation, but a mutant form of syntaxin 1A (A240V, V244A) binds to the channel without functional effect (Bezprozvanny et al, 2000).…”

Familial hemiplegic migraine mutations increase Ca 2+ influx through single human Ca V 2.1 channels and decrease maximal Ca V 2.1 current density in neurons

“…Ca V 2.1 channels are located in presynaptic terminals throughout the brain (13) and play a prominent role in controlling neurotransmitter release at most synapses (14). Their localization in somatodendritic membranes points to additional postsynaptic roles (15)(16)(17). Studies of mutant Ca V 2.1 channels in heterologous expression systems revealed that FHM mutations alter both the single-channel biophysical properties and the density of functional channels in the membrane (18)(19)(20).…”