RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

M Katharina Grauel; Marta Maglione; Suneel Reddy-Alla; Claudia G Willmes; Marisa M Brockmann; Thorsten Trimbuch; Tanja Rosenmund; Maria Pangalos; Gülçin Vardar; Alexander Stumpf; Alexander M Walter; Benjamin R Rost; Britta J Eickholt; Volker Haucke; Dietmar Schmitz; Stephan J Sigrist; Christian Rosenmund

doi:10.1073/pnas.1605256113

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

M Katharina Grauel, Marta Maglione, Suneel Reddy-Alla, Claudia G Willmes, Marisa M Brockmann, Thorsten Trimbuch, Tanja Rosenmund, Maria Pangalos, Gülçin Vardar, Alexander Stumpf, Alexander M Walter, Benjamin R Rost, Britta J Eickholt, Volker Haucke, Dietmar Schmitz, Stephan J Sigrist, Christian Rosenmund

Research output: Contribution to journal › Journal article › Research › peer-review

70 Citations (Scopus)

Abstract

The tight spatial coupling of synaptic vesicles and voltage-gated Ca2+ channels (CaVs) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca2+ channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2-deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased short-term facilitation. Superresolution microscopy revealed an impairment in CaV2.1 clustering at AZs, which likely alters Ca2+ nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	41
Pages (from-to)	11615-11620
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1605256113
Publication status	Published - 11 Oct 2016
Externally published	Yes

Keywords

Action Potentials
Animals
Calcium/metabolism
Calcium Channels/metabolism
Cells, Cultured
Electrophysiological Phenomena
Female
Gene Deletion
Gene Expression
Gene Targeting
Genetic Loci
Hippocampus/metabolism
Male
Mice
Mice, Knockout
Neurons/metabolism
Phenotype
Protein Transport
Synapses/metabolism
Synaptic Transmission/genetics
Synaptic Vesicles/metabolism

Access to Document

10.1073/pnas.1605256113

Cite this

Grauel, M. K., Maglione, M., Reddy-Alla, S., Willmes, C. G., Brockmann, M. M., Trimbuch, T., Rosenmund, T., Pangalos, M., Vardar, G., Stumpf, A., Walter, A. M., Rost, B. R., Eickholt, B. J., Haucke, V., Schmitz, D., Sigrist, S. J., & Rosenmund, C. (2016). RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses. Proceedings of the National Academy of Sciences of the United States of America, 113(41), 11615-11620. https://doi.org/10.1073/pnas.1605256113

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses. / Grauel, M Katharina; Maglione, Marta; Reddy-Alla, Suneel; Willmes, Claudia G; Brockmann, Marisa M; Trimbuch, Thorsten; Rosenmund, Tanja; Pangalos, Maria; Vardar, Gülçin; Stumpf, Alexander; Walter, Alexander M; Rost, Benjamin R; Eickholt, Britta J; Haucke, Volker; Schmitz, Dietmar; Sigrist, Stephan J; Rosenmund, Christian.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 41, 11.10.2016, p. 11615-11620.

Research output: Contribution to journal › Journal article › Research › peer-review

Grauel, MK, Maglione, M, Reddy-Alla, S, Willmes, CG, Brockmann, MM, Trimbuch, T, Rosenmund, T, Pangalos, M, Vardar, G, Stumpf, A, Walter, AM, Rost, BR, Eickholt, BJ, Haucke, V, Schmitz, D, Sigrist, SJ & Rosenmund, C 2016, 'RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 41, pp. 11615-11620. https://doi.org/10.1073/pnas.1605256113

Grauel, M Katharina ; Maglione, Marta ; Reddy-Alla, Suneel ; Willmes, Claudia G ; Brockmann, Marisa M ; Trimbuch, Thorsten ; Rosenmund, Tanja ; Pangalos, Maria ; Vardar, Gülçin ; Stumpf, Alexander ; Walter, Alexander M ; Rost, Benjamin R ; Eickholt, Britta J ; Haucke, Volker ; Schmitz, Dietmar ; Sigrist, Stephan J ; Rosenmund, Christian. / RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 41. pp. 11615-11620.

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AU - Grauel, M Katharina

AU - Maglione, Marta

AU - Reddy-Alla, Suneel

AU - Willmes, Claudia G

AU - Brockmann, Marisa M

AU - Trimbuch, Thorsten

AU - Rosenmund, Tanja

AU - Pangalos, Maria

AU - Vardar, Gülçin

AU - Stumpf, Alexander

AU - Walter, Alexander M

AU - Rost, Benjamin R

AU - Eickholt, Britta J

AU - Haucke, Volker

AU - Schmitz, Dietmar

AU - Sigrist, Stephan J

AU - Rosenmund, Christian

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AB - The tight spatial coupling of synaptic vesicles and voltage-gated Ca2+ channels (CaVs) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca2+ channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2-deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased short-term facilitation. Superresolution microscopy revealed an impairment in CaV2.1 clustering at AZs, which likely alters Ca2+ nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses.

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