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Cell Rep. 2018 Jul 10;24(2):284-293.e6. doi: 10.1016/j.celrep.2018.06.024.

CAST/ELKS Proteins Control Voltage-Gated Ca2+ Channel Density and Synaptic Release Probability at a Mammalian Central Synapse.

Author information

1
Research Group Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA; Key Laboratory of Medical Electrophysiology, Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China.
2
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
3
Max Planck Florida Institute for Neuroscience Electron Microscopy Facility, Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA.
4
Research Group Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA.
5
Department of Biochemistry, University of Yamanashi, Yamanashi 409-3898, Japan.
6
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
7
Department of Biochemistry, University of Yamanashi, Yamanashi 409-3898, Japan. Electronic address: tohtsuka@yamanashi.ac.jp.
8
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA; Department of Otolaryngology, University of Iowa, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA; Aging Mind Brain Initiative, University of Iowa, Iowa City, IA 52242, USA. Electronic address: samuel-m-young@uiowa.edu.

Abstract

In the presynaptic terminal, the magnitude and location of Ca2+ entry through voltage-gated Ca2+ channels (VGCCs) regulate the efficacy of neurotransmitter release. However, how presynaptic active zone proteins control mammalian VGCC levels and organization is unclear. To address this, we deleted the CAST/ELKS protein family at the calyx of Held, a CaV2.1 channel-exclusive presynaptic terminal. We found that loss of CAST/ELKS reduces the CaV2.1 current density with concomitant reductions in CaV2.1 channel numbers and clusters. Surprisingly, deletion of CAST/ELKS increases release probability while decreasing the readily releasable pool, with no change in active zone ultrastructure. In addition, Ca2+ channel coupling is unchanged, but spontaneous release rates are elevated. Thus, our data identify distinct roles for CAST/ELKS as positive regulators of CaV2.1 channel density and suggest that they regulate release probability through a post-priming step that controls synaptic vesicle fusogenicity.

KEYWORDS:

CAST/ELKS; active zone; auditory signaling; calcium channels; calyx of Held; exocytosis; release probability; synaptic transmission

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