[{"OA_place":"repository","date_published":"2026-08-13T00:00:00Z","author":[{"id":"3B59276A-F248-11E8-B48F-1D18A9856A87","first_name":"Elodie","last_name":"Le Monnier","full_name":"Le Monnier, Elodie"},{"first_name":"Cihan","full_name":"Önal, Cihan","last_name":"Önal"}],"corr_author":"1","acknowledged_ssus":[{"_id":"M-Shop"},{"_id":"PreCl"}],"title":"Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula","user_id":"68b8ca59-c5b3-11ee-8790-cd641c68093d","date_created":"2026-08-13T12:20:08Z","oa":1,"file_date_updated":"2026-08-13T13:06:29Z","file":[{"date_created":"2026-08-13T12:07:53Z","file_size":162086,"file_name":"Behavior.zip","file_id":"22705","content_type":"application/x-zip-compressed","access_level":"open_access","relation":"main_file","checksum":"7742bb211a43bb87c2b5ce7bda3068ae","creator":"elemonni","success":1,"date_updated":"2026-08-13T12:07:53Z"},{"date_updated":"2026-08-13T12:07:57Z","creator":"elemonni","relation":"main_file","checksum":"a162eb6103a770d94536374e02934fcf","success":1,"file_id":"22706","file_name":"image_analysis.zip","content_type":"application/x-zip-compressed","access_level":"open_access","file_size":6643,"date_created":"2026-08-13T12:07:57Z"},{"file_name":"Recordings.zip","content_type":"application/x-zip-compressed","access_level":"open_access","file_id":"22707","date_created":"2026-08-13T12:07:59Z","file_size":1193016,"date_updated":"2026-08-13T12:07:59Z","relation":"main_file","creator":"elemonni","success":1,"checksum":"608aaf395bba5fd9cf62d8c8940d63aa"},{"creator":"elemonni","checksum":"2389ebd71238bd7de03d20504a8cf962","success":1,"relation":"main_file","date_updated":"2026-08-13T13:06:29Z","date_created":"2026-08-13T13:06:29Z","file_size":246,"file_name":"README.txt","content_type":"text/plain","file_id":"22708","access_level":"open_access"}],"ec_funded":1,"department":[{"_id":"RySh"}],"year":"2026","project":[{"_id":"2564DBCA-B435-11E9-9278-68D0E5697425","name":"International IST Doctoral Program","grant_number":"665385","call_identifier":"H2020"},{"_id":"92503f6e-16d5-11f0-9cad-8c571927f3b7","name":"New regime of presynaptic release regulation","grant_number":"PAT 5720324"}],"_id":"22704","status":"public","doi_confirm":"1","day":"13","type":"research_data","doi":"10.15479/AT-ISTA-22704","publisher":"Institute of Science and Technology Austria","article_processing_charge":"No","citation":{"ama":"Le Monnier E, Önal C. Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula. 2026. doi:<a href=\"https://doi.org/10.15479/AT-ISTA-22704\">10.15479/AT-ISTA-22704</a>","apa":"Le Monnier, E., &#38; Önal, C. (2026). Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT-ISTA-22704\">https://doi.org/10.15479/AT-ISTA-22704</a>","short":"E. Le Monnier, C. Önal, (2026).","ista":"Le Monnier E, Önal C. 2026. Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula, Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT-ISTA-22704\">10.15479/AT-ISTA-22704</a>.","chicago":"Le Monnier, Elodie, and Cihan Önal. “Asymmetrical Modulation of Fear Expression via GABAB Receptors in the Mouse Medial Habenula.” Institute of Science and Technology Austria, 2026. <a href=\"https://doi.org/10.15479/AT-ISTA-22704\">https://doi.org/10.15479/AT-ISTA-22704</a>.","ieee":"E. Le Monnier and C. Önal, “Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula.” Institute of Science and Technology Austria, 2026.","mla":"Le Monnier, Elodie, and Cihan Önal. <i>Asymmetrical Modulation of Fear Expression via GABAB Receptors in the Mouse Medial Habenula</i>. Institute of Science and Technology Austria, 2026, doi:<a href=\"https://doi.org/10.15479/AT-ISTA-22704\">10.15479/AT-ISTA-22704</a>."},"has_accepted_license":"1","oa_version":"None","tmp":{"image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode"},"month":"08","abstract":[{"text":"The medial habenula (MHb) is implicated in regulating emotional responses to aversive events. Studies in zebrafish have identified a remarkable morphological left–right asymmetry in the dorsal habenula (zebrafish equivalent of mammalian MHb)-interpeduncular nucleus (IPN) pathway and its asymmetrical roles in behavior. However, there is little evidence for structural or functional lateralization in the mammalian MHb-IPN pathway. Here, we investigated the synaptic properties of left- and right-MHb afferents to the IPN and their roles in the expression of conditioned fear in mice. We found that each IPN neuron receives inputs from both left and right MHb, but the left MHb-originating synapses exhibit lower release probability and higher γ-aminobutyric acid type B receptor (GABABR)-mediated potentiation compared to the right MHb-originating synapses. Interestingly, these asymmetrical properties persist in the inversus visceral mutant mice with normal internal organ laterality (situs solitus), but nearly disappear in those with reversed internal organ laterality (situs inversus). Behaviorally, chemogenetic inhibition of cholinergic neurons and conditional deletion of GABABR in the left, but not the right, MHb significantly attenuated cue-dependent fear recall. Our results demonstrate functional asymmetry of the MHb under partial influence of the nodal flow in mice, revealing a predominant role of GABABR-mediated signaling in the left MHb-IPN pathway in modulating fear memories. These findings suggest that lateralized MHb pathways could represent a fundamental principle in the neural regulation of emotion across species but that they develop differently in zebrafish and mice.\r\n","lang":"eng"}],"date_updated":"2026-08-13T13:30:37Z"},{"status":"public","_id":"15084","type":"journal_article","publication_identifier":{"issn":["0027-8424"],"eissn":["1091-6490"]},"article_processing_charge":"Yes (in subscription journal)","citation":{"ama":"Koppensteiner P, Bhandari P, Önal C, et al. GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 2024;121(8). doi:<a href=\"https://doi.org/10.1073/pnas.2301449121\">10.1073/pnas.2301449121</a>","apa":"Koppensteiner, P., Bhandari, P., Önal, C., Borges Merjane, C., Le Monnier, E., Roy, U., … Shigemoto, R. (2024). GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2301449121\">https://doi.org/10.1073/pnas.2301449121</a>","short":"P. Koppensteiner, P. Bhandari, C. Önal, C. Borges Merjane, E. Le Monnier, U. Roy, Y. Nakamura, T. Sadakata, M. Sanbo, M. Hirabayashi, J. Rhee, N. Brose, P.M. Jonas, R. Shigemoto, Proceedings of the National Academy of Sciences of the United States of America 121 (2024).","ista":"Koppensteiner P, Bhandari P, Önal C, Borges Merjane C, Le Monnier E, Roy U, Nakamura Y, Sadakata T, Sanbo M, Hirabayashi M, Rhee J, Brose N, Jonas PM, Shigemoto R. 2024. GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles. Proceedings of the National Academy of Sciences of the United States of America. 121(8), e2301449121.","ieee":"P. Koppensteiner <i>et al.</i>, “GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles,” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 121, no. 8. National Academy of Sciences, 2024.","chicago":"Koppensteiner, Peter, Pradeep Bhandari, Cihan Önal, Carolina Borges Merjane, Elodie Le Monnier, Utsa Roy, Yukihiro Nakamura, et al. “GABAB Receptors Induce Phasic Release from Medial Habenula Terminals through Activity-Dependent Recruitment of Release-Ready Vesicles.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences, 2024. <a href=\"https://doi.org/10.1073/pnas.2301449121\">https://doi.org/10.1073/pnas.2301449121</a>.","mla":"Koppensteiner, Peter, et al. “GABAB Receptors Induce Phasic Release from Medial Habenula Terminals through Activity-Dependent Recruitment of Release-Ready Vesicles.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 121, no. 8, e2301449121, National Academy of Sciences, 2024, doi:<a href=\"https://doi.org/10.1073/pnas.2301449121\">10.1073/pnas.2301449121</a>."},"has_accepted_license":"1","isi":1,"oa_version":"Published Version","tmp":{"image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode"},"article_type":"original","related_material":{"link":[{"url":"https://ista.ac.at/en/news/neuronal-insights-flash-and-freeze-fracture/","relation":"press_release","description":"News on ISTA Website"}],"record":[{"relation":"research_data","status":"public","id":"13173"},{"id":"19271","status":"public","relation":"dissertation_contains"}]},"volume":121,"abstract":[{"lang":"eng","text":"GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation on MHb terminals induces an activity-dependent transition from a facilitating, tonic to a depressing, phasic neurotransmitter release mode. This transition is accompanied by a 4.1-fold increase in readily releasable vesicle pool (RRP) size and a 3.5-fold increase of docked synaptic vesicles (SVs) at the presynaptic active zone (AZ). Strikingly, the depressing phasic release exhibits looser coupling distance than the tonic release. Furthermore, the tonic and phasic release are selectively affected by deletion of synaptoporin (SPO) and Ca\r\n            <jats:sup>2+</jats:sup>\r\n            -dependent activator protein for secretion 2 (CAPS2), respectively. SPO modulates augmentation, the short-term plasticity associated with tonic release, and CAPS2 retains the increased RRP for initial responses in phasic response trains. The cytosolic protein CAPS2 showed a SV-associated distribution similar to the vesicular transmembrane protein SPO, and they were colocalized in the same terminals. We developed the “Flash and Freeze-fracture” method, and revealed the release of SPO-associated vesicles in both tonic and phasic modes and activity-dependent recruitment of CAPS2 to the AZ during phasic release, which lasted several minutes. Overall, these results indicate that GBR activation translocates CAPS2 to the AZ along with the fusion of CAPS2-associated SVs, contributing to persistency of the RRP increase. Thus, we identified structural and molecular mechanisms underlying tonic and phasic neurotransmitter release and their transition by GBR activation in MHb terminals."}],"month":"02","issue":"8","date_updated":"2026-08-31T22:30:37Z","article_number":"e2301449121","date_published":"2024-02-20T00:00:00Z","author":[{"last_name":"Koppensteiner","orcid":"0000-0002-3509-1948","full_name":"Koppensteiner, Peter","id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","first_name":"Peter"},{"id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87","first_name":"Pradeep","last_name":"Bhandari","orcid":"0000-0003-0863-4481","full_name":"Bhandari, Pradeep"},{"first_name":"Hüseyin C","id":"4659D740-F248-11E8-B48F-1D18A9856A87","full_name":"Önal, Hüseyin C","orcid":"0000-0002-2771-2011","last_name":"Önal"},{"id":"4305C450-F248-11E8-B48F-1D18A9856A87","first_name":"Carolina","last_name":"Borges Merjane","orcid":"0000-0003-0005-401X","full_name":"Borges Merjane, Carolina"},{"full_name":"Le Monnier, Elodie","last_name":"Le Monnier","first_name":"Elodie","id":"3B59276A-F248-11E8-B48F-1D18A9856A87"},{"id":"4d26cf11-5355-11ee-ae5a-eb05e255b9b2","first_name":"Utsa","last_name":"Roy","full_name":"Roy, Utsa"},{"full_name":"Nakamura, Yukihiro","last_name":"Nakamura","first_name":"Yukihiro"},{"first_name":"Tetsushi","full_name":"Sadakata, Tetsushi","last_name":"Sadakata"},{"full_name":"Sanbo, Makoto","last_name":"Sanbo","first_name":"Makoto"},{"last_name":"Hirabayashi","full_name":"Hirabayashi, Masumi","first_name":"Masumi"},{"full_name":"Rhee, JeongSeop","last_name":"Rhee","first_name":"JeongSeop"},{"first_name":"Nils","full_name":"Brose, Nils","last_name":"Brose"},{"first_name":"Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","full_name":"Jonas, Peter M","orcid":"0000-0001-5001-4804","last_name":"Jonas"},{"full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto","orcid":"0000-0001-8761-9444","first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87"}],"acknowledged_ssus":[{"_id":"M-Shop"},{"_id":"PreCl"},{"_id":"EM-Fac"}],"title":"GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles","quality_controlled":"1","pmid":1,"file":[{"success":1,"creator":"dernst","checksum":"b25b2a057c266ff317a48b0d54d6fc8a","relation":"main_file","date_updated":"2024-03-12T13:42:42Z","file_size":13648221,"date_created":"2024-03-12T13:42:42Z","content_type":"application/pdf","file_id":"15110","access_level":"open_access","file_name":"2024_PNAS_Koppensteiner.pdf"}],"publication":"Proceedings of the National Academy of Sciences of the United States of America","APC_amount":"5887,8 EUR","publication_status":"published","day":"20","OA_type":"hybrid","doi":"10.1073/pnas.2301449121","publisher":"National Academy of Sciences","acknowledgement":"We thank Erwin Neher and Ipe Ninan for critical comments on the manuscript. This project has received funding from the European Research Council (ERC) and European Commission, under the European Union’s Horizon 2020 research and innovation program (ERC grant agreement no. 694539 to R.S. and the Marie Skłodowska-Curie grant agreement no. 665385 to C.Ö.). This study was supported by the Cooperative Study Program of Center for Animal Resources and Collaborative Study of NINS. We thank Kohgaku Eguchi for statistical analysis, Yu Kasugai for additional EM imaging, Robert Beattie for the design of the slice recovery chamber for Flash and Freeze experiments, Todor Asenov from the ISTA machine shop for custom part preparations for high-pressure freezing, the ISTA preclinical facility for animal caretaking, and the ISTA EM facilities for technical support.","ddc":["570"],"scopus_import":"1","language":[{"iso":"eng"}],"external_id":{"isi":["001208567300006"],"pmid":["38346189"]},"OA_place":"publisher","corr_author":"1","date_created":"2024-03-05T09:23:55Z","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","oa":1,"file_date_updated":"2024-03-12T13:42:42Z","ec_funded":1,"intvolume":"       121","department":[{"_id":"RySh"},{"_id":"PeJo"}],"year":"2024","project":[{"_id":"25CA28EA-B435-11E9-9278-68D0E5697425","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","grant_number":"694539","call_identifier":"H2020"},{"name":"International IST Doctoral Program","_id":"2564DBCA-B435-11E9-9278-68D0E5697425","grant_number":"665385","call_identifier":"H2020"}]},{"scopus_import":"1","ddc":["570"],"acknowledgement":"This work was supported by The Institute of Science and Technology (IST) Austria, the European Union's Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie Grant Agreement No. 793482 (to K.E.) and by the European Research Council (ERC) Grant Agreement No. 694539 (to R.S.). We thank Nicoleta Condruz (IST Austria, Klosterneuburg, Austria) for technical assistance with sample preparation, the Electron Microscopy Facility of IST Austria (Klosterneuburg, Austria) for technical support with EM works, Natalia Baranova (University of Vienna, Vienna, Austria) and Martin Loose (IST Austria, Klosterneuburg, Austria) for advice on liposome preparation, and Yugo Fukazawa (University of Fukui, Fukui, Japan) for comments.","publisher":"Society for Neuroscience","doi":"10.1523/JNEUROSCI.1514-22.2023","day":"07","year":"2023","department":[{"_id":"RySh"}],"intvolume":"        43","project":[{"_id":"2659CC84-B435-11E9-9278-68D0E5697425","name":"Ultrastructural analysis of phosphoinositides in nerve terminals: distribution, dynamics and physiological roles in synaptic transmission","call_identifier":"H2020","grant_number":"793482"},{"name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","grant_number":"694539","call_identifier":"H2020"}],"ec_funded":1,"oa":1,"file_date_updated":"2023-07-10T09:04:58Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_created":"2023-07-09T22:01:12Z","corr_author":"1","language":[{"iso":"eng"}],"external_id":{"pmid":["37160366"],"isi":["001020132100005"]},"abstract":[{"text":"Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) plays an essential role in neuronal activities through interaction with various proteins involved in signaling at membranes. However, the distribution pattern of PI(4,5)P2 and the association with these proteins on the neuronal cell membranes remain elusive. In this study, we established a method for visualizing PI(4,5)P2 by SDS-digested freeze-fracture replica labeling (SDS-FRL) to investigate the quantitative nanoscale distribution of PI(4,5)P2 in cryo-fixed brain. We demonstrate that PI(4,5)P2 forms tiny clusters with a mean size of ∼1000 nm2 rather than randomly distributed in cerebellar neuronal membranes in male C57BL/6J mice. These clusters show preferential accumulation in specific membrane compartments of different cell types, in particular, in Purkinje cell (PC) spines and granule cell (GC) presynaptic active zones. Furthermore, we revealed extensive association of PI(4,5)P2 with CaV2.1 and GIRK3 across different membrane compartments, whereas its association with mGluR1α was compartment specific. These results suggest that our SDS-FRL method provides valuable insights into the physiological functions of PI(4,5)P2 in neurons.","lang":"eng"}],"month":"06","volume":43,"date_updated":"2025-04-14T07:27:15Z","issue":"23","article_type":"original","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png"},"has_accepted_license":"1","isi":1,"oa_version":"Published Version","article_processing_charge":"No","citation":{"mla":"Eguchi, Kohgaku, et al. “Nanoscale Phosphoinositide Distribution on Cell Membranes of Mouse Cerebellar Neurons.” <i>The Journal of Neuroscience</i>, vol. 43, no. 23, Society for Neuroscience, 2023, pp. 4197–216, doi:<a href=\"https://doi.org/10.1523/JNEUROSCI.1514-22.2023\">10.1523/JNEUROSCI.1514-22.2023</a>.","ieee":"K. Eguchi, E. Le Monnier, and R. Shigemoto, “Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons,” <i>The Journal of Neuroscience</i>, vol. 43, no. 23. Society for Neuroscience, pp. 4197–4216, 2023.","chicago":"Eguchi, Kohgaku, Elodie Le Monnier, and Ryuichi Shigemoto. “Nanoscale Phosphoinositide Distribution on Cell Membranes of Mouse Cerebellar Neurons.” <i>The Journal of Neuroscience</i>. Society for Neuroscience, 2023. <a href=\"https://doi.org/10.1523/JNEUROSCI.1514-22.2023\">https://doi.org/10.1523/JNEUROSCI.1514-22.2023</a>.","ista":"Eguchi K, Le Monnier E, Shigemoto R. 2023. Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons. The Journal of Neuroscience. 43(23), 4197–4216.","short":"K. Eguchi, E. Le Monnier, R. Shigemoto, The Journal of Neuroscience 43 (2023) 4197–4216.","apa":"Eguchi, K., Le Monnier, E., &#38; Shigemoto, R. (2023). Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons. <i>The Journal of Neuroscience</i>. Society for Neuroscience. <a href=\"https://doi.org/10.1523/JNEUROSCI.1514-22.2023\">https://doi.org/10.1523/JNEUROSCI.1514-22.2023</a>","ama":"Eguchi K, Le Monnier E, Shigemoto R. Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons. <i>The Journal of Neuroscience</i>. 2023;43(23):4197-4216. doi:<a href=\"https://doi.org/10.1523/JNEUROSCI.1514-22.2023\">10.1523/JNEUROSCI.1514-22.2023</a>"},"type":"journal_article","publication_identifier":{"issn":["0270-6474"],"eissn":["1529-2401"]},"_id":"13202","status":"public","publication_status":"published","page":"4197-4216","publication":"The Journal of Neuroscience","file":[{"checksum":"70b2141870e0bf1c94fd343e18fdbc32","creator":"alisjak","relation":"main_file","success":1,"date_updated":"2023-07-10T09:04:58Z","date_created":"2023-07-10T09:04:58Z","file_size":7794425,"content_type":"application/pdf","access_level":"open_access","file_id":"13205","file_name":"2023_JN_Eguchi.pdf"}],"quality_controlled":"1","pmid":1,"title":"Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons","date_published":"2023-06-07T00:00:00Z","acknowledged_ssus":[{"_id":"EM-Fac"}],"author":[{"orcid":"0000-0002-6170-2546","last_name":"Eguchi","full_name":"Eguchi, Kohgaku","id":"2B7846DC-F248-11E8-B48F-1D18A9856A87","first_name":"Kohgaku"},{"id":"3B59276A-F248-11E8-B48F-1D18A9856A87","first_name":"Elodie","last_name":"Le Monnier","full_name":"Le Monnier, Elodie"},{"id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi","last_name":"Shigemoto","orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi"}]},{"acknowledgement":"We thank Kayla Templeton and Peter Turcanu for technical assistance, Michelle Salemi for assistance with LC-MS data acquisition and analysis, Dr. Belvin Gong for advice on monoclonal antibody generation, Drs. Maria Casas Prat and Eamonn Dickson for assistance with super-resolution TIRF microscopy, Dr. Oscar Cerda for assistance with the design of TAT-FFAT peptides, Dr. Fernando Santana for helpful discussions, and Dr. Jodi Nunnari for a careful reading of our manuscript. We also thank Dr. Alan Howe, Dr. Sohum Mehta, and Dr. Jin Zhang for providing plasmids used in this study. This project was funded by NIH Grants R01NS114210 and R21NS101648 (J.S.T.), and F32NS108519 (N.C.V.).","ddc":["570"],"scopus_import":"1","day":"26","doi":"10.1038/s41467-023-40930-6","publisher":"Springer Nature","year":"2023","intvolume":"        14","department":[{"_id":"RySh"}],"language":[{"iso":"eng"}],"external_id":{"pmid":["37633939"],"isi":["001064563400013"]},"user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","date_created":"2023-09-03T22:01:14Z","oa":1,"file_date_updated":"2023-09-06T06:50:07Z","has_accepted_license":"1","oa_version":"Published Version","isi":1,"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png"},"article_type":"original","abstract":[{"lang":"eng","text":"Junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are specialized membrane contacts ubiquitous in eukaryotic cells. Concentration of intracellular signaling machinery near ER-PM junctions allows these domains to serve critical roles in lipid and Ca2+ signaling and homeostasis. Subcellular compartmentalization of protein kinase A (PKA) signaling also regulates essential cellular functions, however, no specific association between PKA and ER-PM junctional domains is known. Here, we show that in brain neurons type I PKA is directed to Kv2.1 channel-dependent ER-PM junctional domains via SPHKAP, a type I PKA-specific anchoring protein. SPHKAP association with type I PKA regulatory subunit RI and ER-resident VAP proteins results in the concentration of type I PKA between stacked ER cisternae associated with ER-PM junctions. This ER-associated PKA signalosome enables reciprocal regulation between PKA and Ca2+ signaling machinery to support Ca2+ influx and excitation-transcription coupling. These data reveal that neuronal ER-PM junctions support a receptor-independent form of PKA signaling driven by membrane depolarization and intracellular Ca2+, allowing conversion of information encoded in electrical signals into biochemical changes universally recognized throughout the cell."}],"month":"08","volume":14,"date_updated":"2025-09-09T12:50:49Z","status":"public","_id":"14253","type":"journal_article","publication_identifier":{"eissn":["2041-1723"]},"article_processing_charge":"Yes","citation":{"mla":"Vierra, Nicholas C., et al. “Neuronal ER-Plasma Membrane Junctions Couple Excitation to Ca2+-Activated PKA Signaling.” <i>Nature Communications</i>, vol. 14, 5231, Springer Nature, 2023, doi:<a href=\"https://doi.org/10.1038/s41467-023-40930-6\">10.1038/s41467-023-40930-6</a>.","ieee":"N. C. Vierra <i>et al.</i>, “Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling,” <i>Nature Communications</i>, vol. 14. Springer Nature, 2023.","chicago":"Vierra, Nicholas C., Luisa Ribeiro-Silva, Michael Kirmiz, Deborah Van Der List, Pradeep Bhandari, Olivia A. Mack, James Carroll, et al. “Neuronal ER-Plasma Membrane Junctions Couple Excitation to Ca2+-Activated PKA Signaling.” <i>Nature Communications</i>. Springer Nature, 2023. <a href=\"https://doi.org/10.1038/s41467-023-40930-6\">https://doi.org/10.1038/s41467-023-40930-6</a>.","ista":"Vierra NC, Ribeiro-Silva L, Kirmiz M, Van Der List D, Bhandari P, Mack OA, Carroll J, Le Monnier E, Aicher SA, Shigemoto R, Trimmer JS. 2023. Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling. Nature Communications. 14, 5231.","short":"N.C. Vierra, L. Ribeiro-Silva, M. Kirmiz, D. Van Der List, P. Bhandari, O.A. Mack, J. Carroll, E. Le Monnier, S.A. Aicher, R. Shigemoto, J.S. Trimmer, Nature Communications 14 (2023).","apa":"Vierra, N. C., Ribeiro-Silva, L., Kirmiz, M., Van Der List, D., Bhandari, P., Mack, O. A., … Trimmer, J. S. (2023). Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling. <i>Nature Communications</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41467-023-40930-6\">https://doi.org/10.1038/s41467-023-40930-6</a>","ama":"Vierra NC, Ribeiro-Silva L, Kirmiz M, et al. Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling. <i>Nature Communications</i>. 2023;14. doi:<a href=\"https://doi.org/10.1038/s41467-023-40930-6\">10.1038/s41467-023-40930-6</a>"},"quality_controlled":"1","pmid":1,"file":[{"access_level":"open_access","file_id":"14270","content_type":"application/pdf","file_name":"2023_NatureComm_Vierra.pdf","date_created":"2023-09-06T06:50:07Z","file_size":9412549,"date_updated":"2023-09-06T06:50:07Z","success":1,"creator":"dernst","checksum":"6ab8aab4e957f626a09a1c73db3388fb","relation":"main_file"}],"publication":"Nature Communications","publication_status":"published","article_number":"5231","date_published":"2023-08-26T00:00:00Z","author":[{"last_name":"Vierra","full_name":"Vierra, Nicholas C.","first_name":"Nicholas C."},{"first_name":"Luisa","full_name":"Ribeiro-Silva, Luisa","last_name":"Ribeiro-Silva"},{"full_name":"Kirmiz, Michael","last_name":"Kirmiz","first_name":"Michael"},{"full_name":"Van Der List, Deborah","last_name":"Van Der List","first_name":"Deborah"},{"last_name":"Bhandari","orcid":"0000-0003-0863-4481","full_name":"Bhandari, Pradeep","id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87","first_name":"Pradeep"},{"first_name":"Olivia A.","last_name":"Mack","full_name":"Mack, Olivia A."},{"first_name":"James","full_name":"Carroll, James","last_name":"Carroll"},{"last_name":"Le Monnier","full_name":"Le Monnier, Elodie","id":"3B59276A-F248-11E8-B48F-1D18A9856A87","first_name":"Elodie"},{"first_name":"Sue A.","last_name":"Aicher","full_name":"Aicher, Sue A."},{"full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto","orcid":"0000-0001-8761-9444","first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87"},{"first_name":"James S.","last_name":"Trimmer","full_name":"Trimmer, James S."}],"title":"Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling"},{"publication_status":"published","file":[{"date_updated":"2022-03-21T09:41:19Z","checksum":"51ec9b90e7da919e22c01a15489eaacd","creator":"dernst","success":1,"relation":"main_file","access_level":"open_access","content_type":"application/pdf","file_id":"10911","file_name":"2022_FrontiersNeuroanatomy_Eguchi.pdf","file_size":2416395,"date_created":"2022-03-21T09:41:19Z"}],"publication":"Frontiers in Neuroanatomy","quality_controlled":"1","pmid":1,"title":"The number and distinct clustering patterns of voltage-gated Calcium channels in nerve terminals","article_number":"846615","date_published":"2022-02-24T00:00:00Z","author":[{"first_name":"Kohgaku","id":"2B7846DC-F248-11E8-B48F-1D18A9856A87","full_name":"Eguchi, Kohgaku","last_name":"Eguchi","orcid":"0000-0002-6170-2546"},{"full_name":"Montanaro-Punzengruber, Jacqueline-Claire","last_name":"Montanaro-Punzengruber","first_name":"Jacqueline-Claire","id":"3786AB44-F248-11E8-B48F-1D18A9856A87"},{"id":"3B59276A-F248-11E8-B48F-1D18A9856A87","first_name":"Elodie","last_name":"Le Monnier","full_name":"Le Monnier, Elodie"},{"full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto","orcid":"0000-0001-8761-9444","first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87"}],"abstract":[{"text":"Upon the arrival of action potentials at nerve terminals, neurotransmitters are released from synaptic vesicles (SVs) by exocytosis. CaV2.1, 2.2, and 2.3 are the major subunits of the voltage-gated calcium channel (VGCC) responsible for increasing intraterminal calcium levels and triggering SV exocytosis in the central nervous system (CNS) synapses. The two-dimensional analysis of CaV2 distributions using sodium dodecyl sulfate (SDS)-digested freeze-fracture replica labeling (SDS-FRL) has revealed their numbers, densities, and nanoscale clustering patterns in individual presynaptic active zones. The variation in these properties affects the coupling of VGCCs with calcium sensors on SVs, synaptic efficacy, and temporal precision of transmission. In this study, we summarize how the morphological parameters of CaV2 distribution obtained using SDS-FRL differ depending on the different types of synapses and could correspond to functional properties in synaptic transmission.","lang":"eng"}],"month":"02","volume":16,"date_updated":"2026-04-16T08:18:54Z","article_type":"original","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png"},"has_accepted_license":"1","isi":1,"oa_version":"Published Version","article_processing_charge":"No","citation":{"apa":"Eguchi, K., Montanaro-Punzengruber, J.-C., Le Monnier, E., &#38; Shigemoto, R. (2022). The number and distinct clustering patterns of voltage-gated Calcium channels in nerve terminals. <i>Frontiers in Neuroanatomy</i>. Frontiers. <a href=\"https://doi.org/10.3389/fnana.2022.846615\">https://doi.org/10.3389/fnana.2022.846615</a>","ama":"Eguchi K, Montanaro-Punzengruber J-C, Le Monnier E, Shigemoto R. The number and distinct clustering patterns of voltage-gated Calcium channels in nerve terminals. <i>Frontiers in Neuroanatomy</i>. 2022;16. doi:<a href=\"https://doi.org/10.3389/fnana.2022.846615\">10.3389/fnana.2022.846615</a>","chicago":"Eguchi, Kohgaku, Jacqueline-Claire Montanaro-Punzengruber, Elodie Le Monnier, and Ryuichi Shigemoto. “The Number and Distinct Clustering Patterns of Voltage-Gated Calcium Channels in Nerve Terminals.” <i>Frontiers in Neuroanatomy</i>. Frontiers, 2022. <a href=\"https://doi.org/10.3389/fnana.2022.846615\">https://doi.org/10.3389/fnana.2022.846615</a>.","ieee":"K. Eguchi, J.-C. Montanaro-Punzengruber, E. Le Monnier, and R. Shigemoto, “The number and distinct clustering patterns of voltage-gated Calcium channels in nerve terminals,” <i>Frontiers in Neuroanatomy</i>, vol. 16. Frontiers, 2022.","mla":"Eguchi, Kohgaku, et al. “The Number and Distinct Clustering Patterns of Voltage-Gated Calcium Channels in Nerve Terminals.” <i>Frontiers in Neuroanatomy</i>, vol. 16, 846615, Frontiers, 2022, doi:<a href=\"https://doi.org/10.3389/fnana.2022.846615\">10.3389/fnana.2022.846615</a>.","short":"K. Eguchi, J.-C. Montanaro-Punzengruber, E. Le Monnier, R. Shigemoto, Frontiers in Neuroanatomy 16 (2022).","ista":"Eguchi K, Montanaro-Punzengruber J-C, Le Monnier E, Shigemoto R. 2022. The number and distinct clustering patterns of voltage-gated Calcium channels in nerve terminals. Frontiers in Neuroanatomy. 16, 846615."},"type":"journal_article","publication_identifier":{"eissn":["1662-5129"]},"status":"public","_id":"10890","year":"2022","intvolume":"        16","department":[{"_id":"RySh"}],"project":[{"_id":"25CA28EA-B435-11E9-9278-68D0E5697425","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","grant_number":"694539","call_identifier":"H2020"},{"grant_number":"I04638","_id":"05970B30-7A3F-11EA-A408-12923DDC885E","name":"LGI1 antibody-induced pathophysiology in synapses"}],"ec_funded":1,"oa":1,"file_date_updated":"2022-03-21T09:41:19Z","date_created":"2022-03-20T23:01:39Z","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","corr_author":"1","language":[{"iso":"eng"}],"external_id":{"isi":["000766662700001"],"pmid":["35280978"]},"scopus_import":"1","ddc":["570"],"acknowledgement":"This work was supported by the European Research Council advanced grant No. 694539 and the joint German-Austrian DFG and FWF project SYNABS (FWF: I-4638-B) to RS.\r\nThe authors thank Walter Kaufmann for his critical comments on the manuscript.","publisher":"Frontiers","doi":"10.3389/fnana.2022.846615","day":"24"}]