{"doi":"10.1101/2025.01.08.631979","title":"CaMKII clusters neuronal LTCCs in biomolecular condensates to gate excitation-transcription coupling","abstract":"Abstract Neuronal depolarization activates L-type voltage-gated Ca²⁺ channels (LTCCs), increasing local Ca²⁺ concentrations to initiate excitation-transcription (E-T) coupling. We show that depolarization enhances clustering of Ca V 1.2 and Ca V 1.3 LTCCs in cultured hippocampal neurons, coinciding with increased nuclear CREB phosphorylation. LTCC clustering and LTCC-dependent CREB phosphorylation are selectively disrupted by 1,6-hexanediol, implicating biomolecular condensation. Activated CaMKIIα holoenzymes assemble complexes containing multiple Ca V 1.2 and/or Ca V 1.3 α1 subunits. Complex assembly is facilitated by co-expression of CaMKII-binding β2a subunits and Shank3 and selectively disrupted by 1,6-hexanediol. In HEK293 cells, pharmacological LTCC activation enhances clustering only when wild-type CaMKIIα is co-expressed. A CaMKII mutant that cannot bind LTCC N-terminal domains fails to support LTCC subunit complex formation in vitro and LTCC clustering in HEK293 cells. In neurons, the knockdown of CaMKII expression disrupts depolarization-induced (co-)clustering of Ca V 1.2 and Ca V 1.3. Together, these findings indicate that CaMKII-dependent clustering of plasma membrane LTCCs via biomolecular condensation is essential for initiating long-range signaling to activate gene expression following neuronal depolarization.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":560159,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":346920,"name":"Xiaohan Wang","orcid":"0000-0001-7895-2333","position":1,"is_corresponding":false},{"id":1044183,"name":"Lan Hu","orcid":"0009-0002-4383-7655","position":2,"is_corresponding":false},{"id":1462498,"name":"Dorian Lawson-Qureshi","orcid":null,"position":3,"is_corresponding":false},{"id":64616,"name":"Roger J. Colbran","orcid":"0000-0001-7401-8244","position":4,"is_corresponding":false},{"id":1112718,"name":"Qian Yang","orcid":"0000-0001-9861-2790","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T02:55:42.883572Z","pmid":"39829809","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}