{"doi":"10.1101/2020.11.07.372623","title":"Epilepsy-associated Mutations in the Calcium-sensing Receptor Disrupt the Regulation of NALCN Sodium-leak Channel by Extracellular Calcium in Neurons","abstract":"Abstract Most mammalian neurons have a resting membrane potential (RMP) of ~ −50 mV to −70 mV, significantly above the equilibrium potential of K + (E K ) of ~ −90 mV. The resting Na + -leak conductance is a major mechanism by which neurons maintain their RMPs above E K . In the hippocampal neurons, the TTX-insensitive, voltage-independent Na + leak is mediated by the NALCN cation channel. Extracellular Ca 2+ (Ca 2+ e ) also controls the sizes of NALCN current (I NALCN ) in a G-protein-dependent fashion. The molecular identities of the basal Na + conductances and their regulation in other regions in the central nervous system and in the peripheral nervous system are less established. Here we show that neurons cultured from mouse cortices, ventral tegmental area, spinal cord and dorsal root ganglia all have a NALCN-dependent basal Na + -leak conductance that is absent in NALCN knockout mice. Like in hippocampal neurons, a decrease in [Ca 2+ ] e increases I NALCN . Using shRNA knockdown, we show that the regulation of I NALCN by Ca 2+ e in neurons requires the Ca 2+ -sensing G-protein-coupled receptor CaSR. Surprisingly, the functional coupling from [Ca 2+ ] e to NALCN requires CaSR’s distal C-terminal domain that is dispensable for the receptor’s ability to couple [Ca 2+ ] e to its canonical signaling targets such as PLC and MAPK. In addition, several epilepsy-associated human CaSR mutations, though sparing the receptor’s ability to sense Ca 2+ e to maintain systemic [Ca 2+ ], disrupt the ability of CaSR to regulate NALCN. These findings uncover a unique mechanism by which CaSR regulates neuronal excitability via NALCN in the central and peripheral nervous system.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127661,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9461,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":577054,"name":"Boxun Lu","orcid":"0000-0002-1675-9340","position":1,"is_corresponding":false},{"id":497341,"name":"Dejian Ren","orcid":"0000-0002-6592-9457","position":2,"is_corresponding":false},{"id":577053,"name":"Chunlei Cang","orcid":"0000-0002-3302-0927","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-18T23:15:34.966380Z","pmid":null,"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":[]}