Abstract
Spatial and temporal changes in intracellular calcium concentrations are critical for controlling gene expression in neurons1,2,3,4,5. 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 pathway6,7,8,9,10,11. Here we show that selective influx of calcium through P/Q-type channels12,13,14 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.
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Acknowledgements
We thank M. Gilbert, C. Santi, A. Stea and G. Zamponi for comments and discussions. We also thank W. Honer for providing the SP8 human syntaxin-1A monoclonal antibody and D. Brink and V. Leuranguer for tissue culture support. The research was supported by grants from the Medical Research Council (MRC) of Canada (T.P.S. and T.H.M.), postdoctoral support from the Amyotrophic Lateral Sclerosis Society of Canada (K.S.), and studentship and postdoctoral fellowship support from the MRC (H.G. and J.M., respectively). T.P.S. and T.H.M. are recipients of MRC of Canada Scientist awards.
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Sutton, K., McRory, J., Guthrie, H. et al. P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-1A. Nature 401, 800–804 (1999). https://doi.org/10.1038/44586
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DOI: https://doi.org/10.1038/44586
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