{"doi":"10.1101/2020.04.15.043414","title":"Electrical Automaticity and Intercellular Synchronization via Shared Extracellular Compartments","abstract":"ABSTRACT Electrically excitable cells often spontaneously and synchronously depolarize in vitro and in vivo. It remains unknown how cells synchronize and autorhythmically activate above the intrinsic mean activation frequency of isolated cells without pacemaking mechanisms. Recent insights into ephaptic coupling (non-gap junction or synaptic coupling) suggest that cyclic ion accumulation and depletion in diffusion limited extracellular volumes densely expressing ion channels modifies action potentials. This report explores how potassium accumulation and depletion in a restricted extracellular domain promotes spontaneous oscillations in the Hodgkin Huxley action potential model, which does not spontaneously activate on its own without external stimulus. Simulations demonstrate cells sharing a diffusion limited extracellular compartment can become autorhythmic and synchronous despite intercellular electrical heterogeneity. Autorhythmic frequency can be determined by net potassium flux into the cleft and the cleft volume. Additionally, inexcitable cells can induce autorhythmic activity in an excitable cell via a shared cleft and sufficient potassium fluxes contributed by each cell. Importantly, the synchronization and autorhythmic activity conferred by shared cleft with reduced potassium efflux can occur in the absence of gap junctions. Lastly, not only can potassium oscillations in shared restricted clefts initiate, support, and suppress autorhythmic depolarizations, the same mechanism can homogenize repolarization. The work has implications for understanding how automaticity is coordinated among excitable cells and suggests a new role for non-excitable cells such as fibroblasts, macrophages, or astrocytes with sarcolemmal potassium handling proteins facing shared and restricted intercellular clefts. SIGNIFICANCE A mechanism of cyclic ion accumulation and depletion in diffusion limited extracellular compartments can suppress, initiate, and support autorhythmic activity. Additionally, autorhythmicity can emerge from electrophysiologically heterogeneous cell pairs sharing a diffusion limited extracellular compartment, even if the individual cells will not spontaneously depolarize on their own. Sustained and synchronous autorhythmic activity can occur in the absence of gap junction coupling. Lastly, the shared diffusion limited extracellular compartment can also reduce action potential duration gradients by synchronizing repolarization.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126518,"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":0.9575,"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":573986,"name":"James P. Keener","orcid":"0000-0001-9216-4157","position":1,"is_corresponding":false},{"id":284924,"name":"Steven Poelzing","orcid":"0000-0002-6979-1264","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-18T23:15:23.509897Z","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":[]}