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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,27]]},"abstract":"<jats:p>\n                    The abundance of CaV2 voltage-gated calcium channels is linked to presynaptic homeostatic plasticity (PHP), a process that recalibrates synaptic strength to maintain the stability of neural circuits. However, the molecular and cellular mechanisms governing PHP and CaV2 channels are not completely understood. Here, we uncover a previously not described form of PHP in\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , revealing an inverse regulatory relationship between the efficiency of neurotransmitter release and the abundance of UNC-2\/CaV2 channels. Gain-of-function\n                    <jats:italic>unc-2SL(S240L)<\/jats:italic>\n                    mutants, which carry a mutation analogous to the one causing familial hemiplegic migraine type 1 in humans, showed markedly reduced channel abundance despite increased channel functionality. Reducing synaptic release in these\n                    <jats:italic>unc-2SL(S240L)<\/jats:italic>\n                    mutants restored channel levels to those observed in wild-type animals. Conversely, loss-of-function\n                    <jats:italic>unc-2DA(D726A)<\/jats:italic>\n                    mutants, which harbor the D726A mutation in the channel pore, exhibited a marked increase in channel abundance. Enhancing synaptic release in\n                    <jats:italic>unc-2DA<\/jats:italic>\n                    mutants reversed this increase in channel levels. Importantly, this homeostatic regulation of UNC-2 channel levels is accompanied by the structural remodeling of the active zone (AZ); specifically,\n                    <jats:italic>unc-2DA<\/jats:italic>\n                    mutants, which exhibit increased channel abundance, showed parallel increases in select AZ proteins. Finally, our forward genetic screen revealed that WWP-1, a HECT family E3 ubiquitin ligase, is a key homeostatic mediator that removes UNC-2 from synapses. These findings highlight a self-tuning PHP regulating UNC-2\/CaV2 channel abundance along with AZ reorganization, ensuring synaptic strength and stability.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2404969121","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T13:43:41Z","timestamp":1724334221000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Presynaptic neurons self-tune by inversely coupling neurotransmitter release with the abundance of CaV2 voltage-gated Ca\n                    <sup>2+<\/sup>\n                    channels"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2365-5061","authenticated-orcid":false,"given":"Ame","family":"Xiong","sequence":"first","affiliation":[{"name":"Discipline of Cell Biology &amp; Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet E.","family":"Richmond","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Illinois, Chicago, IL 60607"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4879-7122","authenticated-orcid":false,"given":"Hongkyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Discipline of Cell Biology &amp; Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a005736"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.09.044"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.05.009"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0903603106"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00107.2006"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/36103"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021014-071740"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2018.10.003"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010818-021757"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/function\/zqaa027"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15759"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2020.03.008"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0076-21.2021"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyac176"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08977-6"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.11.028"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.02203"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201106036"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-420138-5.00019-7"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.81407"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.115.184275"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38595-2"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.45905"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2526-13.2014"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.08.079"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.01.011"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80415-8"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80458-4"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.34338"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05473"},{"key":"e_1_3_4_31_2","first-page":"2416","article-title":"Endogenous tagging reveals differential regulation of Ca(2+) channels at single active zones during presynaptic homeostatic potentiation and depression","volume":"39","author":"Gratz S. 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