Protein kinase C is a calcium sensor for presynaptic short-term plasticity.

Yunxiang Chu,Diasynou Fioravante,Michael Leitges,Pascal S Kaeser,Wade G Regehr,Arthur Ph De Jong

doi:10.7554/elife.03011

Yunxiang Chu, Diasynou Fioravante + Show 4 more

Open Access

https://doi.org/10.7554/elife.03011

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Abstract

In presynaptic boutons, calcium (Ca(2+)) triggers both neurotransmitter release and short-term synaptic plasticity. Whereas synaptotagmins are known to mediate vesicle fusion through binding of high local Ca(2+) to their C2 domains, the proteins that sense smaller global Ca(2+) increases to produce short-term plasticity have remained elusive. Here, we identify a Ca(2+) sensor for post-tetanic potentiation (PTP), a form of plasticity thought to underlie short-term memory. We find that at the functionally mature calyx of Held synapse the Ca(2+)-dependent protein kinase C isoforms α and β are necessary for PTP, and the expression of PKCβ in PKCαβ double knockout mice rescues PTP. Disruption of Ca(2+) binding to the PKCβ C2 domain specifically prevents PTP without impairing other PKCβ-dependent forms of synaptic enhancement. We conclude that different C2-domain-containing presynaptic proteins are engaged by different Ca(2+) signals, and that Ca(2+) increases evoked by tetanic stimulation are sensed by PKCβ to produce PTP.DOI: http://dx.doi.org/10.7554/eLife.03011.001.

Highlights

The complex manner in which patterns of action potentials (AP) are transformed into neurotransmitter release suggests the existence of multiple presynaptic calcium (Ca2+) sensors (Kaeser and Regehr, 2013)
Post-tetanic potentiation is a short-term increase in strength that lasts for tens of seconds: it is triggered by a calcium increase in the presynaptic cell and involves an increase in the amount of neurotransmitter released in response to each presynaptic action potential
We further tested whether the contribution of PKCCa to a related form of potentiation that occludes post-tetanic potentiation (PTP) increases with development

Summary

Introduction

The complex manner in which patterns of action potentials (AP) are transformed into neurotransmitter release suggests the existence of multiple presynaptic calcium (Ca2+) sensors (Kaeser and Regehr, 2013). For a widespread form of short-term plasticity termed post-tetanic potentiation (PTP), a high-frequency burst of presynaptic APs enhances subsequent AP-evoked release for tens of seconds. Three Ca2+-dependent isoforms of protein kinase C (PKCCa; PKCα, PKCβ, and PKCγ) play crucial roles in PTP (Fioravante et al, 2011, 2012; Chu et al, 2014) Because these isoforms contain Ca2+binding C2 domains (Shao et al, 1996; Sutton and Sprang, 1998), we hypothesize that they function as Ca2+ sensors for PTP. Post-tetanic potentiation is a short-term increase in strength that lasts for tens of seconds: it is triggered by a calcium increase in the presynaptic cell and involves an increase in the amount of neurotransmitter released in response to each presynaptic action potential. In order to determine whether PKCCa isoforms are Ca2+ sensors that mediate PTP, it must be determined if PTP relies on Ca2+ binding to the PKCCa C2 domain

Results

Discussion

Materials and methods