{"doi":"10.1073/pnas.2205874119","title":"Flux coupling, not specificity, shapes the transport and phylogeny of SLC6 glycine transporters","abstract":"ATB <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mrow> <mml:mn>0</mml:mn> <mml:mo>,</mml:mo> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:mrow> </mml:math> ( SLC6A14 ) is a member of the amino acid transporter branch of the SLC6 family along with GlyT1 ( SLC6A9 ) and GlyT2 ( SLC6A5 ), two glycine-specific transporters coupled to 2:1 and 3:1 Na <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mo>+</mml:mo> </mml:msup> </mml:mrow> </mml:math> :Cl <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mo>−</mml:mo> </mml:msup> </mml:mrow> </mml:math> , respectively. In contrast, ATB <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mrow> <mml:mn>0</mml:mn> <mml:mo>,</mml:mo> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:mrow> </mml:math> exhibits broad substrate specificity for all neutral and cationic amino acids, and its ionic coupling remains unsettled. Using the reversal potential slope method, we demonstrate a 3:1:1 Na <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mo>+</mml:mo> </mml:msup> </mml:mrow> </mml:math> :Cl <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mo>−</mml:mo> </mml:msup> </mml:mrow> </mml:math> :Gly stoichiometry for ATB <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mrow> <mml:mn>0</mml:mn> <mml:mo>,</mml:mo> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:mrow> </mml:math> that is consistent with its 2.1 e /Gly charge coupling. Like GlyT2, ATB <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mrow> <mml:mn>0</mml:mn> <mml:mo>,</mml:mo> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:mrow> </mml:math> behaves as a unidirectional transporter with virtually no glycine efflux at negative potentials after uptake, except by heteroexchange as remarkably shown by leucine activation of NMDARs in Xenopus oocytes coexpressing both membrane proteins. Analysis and computational modeling of the charge movement of ATB <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mrow> <mml:mn>0</mml:mn> <mml:mo>,</mml:mo> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:mrow> </mml:math> reveal a higher affinity for sodium in the absence of substrate than GlyT2 and a gating mechanism that locks Na <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mo>+</mml:mo> </mml:msup> </mml:mrow> </mml:math> into the apo-transporter at depolarized potentials. A 3:1 Na <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mo>+</mml:mo> </mml:msup> </mml:mrow> </mml:math> :Cl <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mo>−</mml:mo> </mml:msup> </mml:mrow> </mml:math> stoichiometry justifies the concentrative transport properties of ATB <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mrow/> <mml:mrow> <mml:mn>0</mml:mn> <mml:mo>,</mml:mo> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:mrow> </mml:math> and explains its trophic role in tumor growth, while rationalizing its phylogenetic proximity to GlyT2 despite their extreme divergence in specificity.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":274474,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9517,"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":943579,"name":"France Rousseau","orcid":null,"position":1,"is_corresponding":false},{"id":942990,"name":"Marion Bied","orcid":"0000-0002-6467-4552","position":2,"is_corresponding":false},{"id":942991,"name":"Stéphane Supplisson","orcid":"0000-0002-0062-9752","position":3,"is_corresponding":false},{"id":942989,"name":"Bastien Le Guellec","orcid":"0000-0002-3618-4791","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-19T00:28:12.324621Z","pmid":"36191186","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":[]}