{"doi":"10.1073/pnas.2120870119","title":"TRPC4 and GIRK channels underlie neuronal coding of firing patterns that reflect G <sub>q/11</sub> –G <sub>i/o</sub> coincidence signals of variable strengths","abstract":"Transient receptor potential canonical 4 (TRPC4) is a receptor-operated cation channel codependent on both the Gq/11–phospholipase C signaling pathway and Gi/o proteins for activation. This makes TRPC4 an excellent coincidence sensor of neurotransmission through Gq/11- and Gi/o-coupled receptors. In whole-cell slice recordings of lateral septal neurons, TRPC4 mediates a strong depolarizing plateau that shuts down action potential firing, which may or may not be followed by a hyperpolarization that extends the firing pause to varying durations depending on the strength of Gi/o stimulation. We show that the depolarizing plateau is codependent on Gq/11-coupled group I metabotropic glutamate receptors and on Gi/o-coupled γ-aminobutyric acid type B receptors. The hyperpolarization is mediated by Gi/o activation of G protein–activated inwardly rectifying K+ (GIRK) channels. Moreover, the firing patterns, elicited by either electrical stimulation or receptor agonists, encode information about the relative strengths of Gq/11 and Gi/o inputs in the following fashion. Pure Gq/11 input produces weak depolarization accompanied by firing acceleration, whereas pure Gi/o input causes hyperpolarization that pauses firing. Although coincident Gq/11–Gi/o inputs also pause firing, the pause is preceded by a burst, and both the pause duration and firing recovery patterns reflect the relative strengths of Gq/11 versus Gi/o inputs. Computer simulations demonstrate that different combinations of TRPC4 and GIRK conductances are sufficient to produce the range of firing patterns observed experimentally. Thus, concurrent neurotransmission through the Gq/11 and Gi/o pathways is converted to discernible electrical responses by the joint actions of TRPC4 and GIRK for communication to downstream neurons.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":256426,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9521,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":905267,"name":"Jane Yang","orcid":"0000-0003-0114-5503","position":1,"is_corresponding":false},{"id":905268,"name":"William C. Joslin","orcid":"0000-0002-2401-228X","position":2,"is_corresponding":false},{"id":905269,"name":"Veit Flockerzi","orcid":"0000-0001-6002-6294","position":3,"is_corresponding":false},{"id":881750,"name":"Steven A. Prescott","orcid":"0000-0002-3827-4512","position":4,"is_corresponding":false},{"id":110422,"name":"Lutz Birnbaumer","orcid":"0000-0002-0775-8661","position":5,"is_corresponding":false},{"id":243371,"name":"Michael X. Zhu","orcid":"0000-0002-5676-841X","position":6,"is_corresponding":false},{"id":243367,"name":"Jinbin Tian","orcid":"0000-0002-5516-7778","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T00:25:21.336200Z","pmid":"35544691","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":[]}