Ma, ZhongmingTaruno, AkiyukiOhmoto, MakotoJyotaki, MasafumiLim, Jason C.Miyazaki, HiroakiNiisato, NaomiMarunaka, YoshinoriLee, Robert J.Hoff, HenryPayne, RileyDemuro, AngeloParker, IanMitchell, Claire H.Henao-Mejia, JorgeTanis, Jessica E.Matsumoto, IchiroTordoff, Michael G.Foskett, Kevin J.2023-05-222023-05-222018-05-022022-06-30https://repository.upenn.edu/handle/20.500.14332/9232Binding of sweet, umami, and bitter tastants to G protein-coupled receptors (GPCRs) in apical membranes of type II taste bud cells (TBCs) triggers action potentials that activate a voltage-gated nonselective ion channel to release ATP to gustatory nerves mediating taste perception. Although calcium homeostasis modulator 1 (CALHM1) is necessary for ATP release, the molecular identification of the channel complex that provides the conductive ATP-release mechanism suitable for action potential-dependent neurotransmission remains to be determined. Here we show that CALHM3 interacts with CALHM1 as a pore-forming subunit in a CALHM1/CALHM3 hexameric channel, endowing it with fast voltage-activated gating identical to that of the ATP-release channel in vivo. Calhm3 is co-expressed with Calhm1 exclusively in type II TBCs, and its genetic deletion abolishes taste-evoked ATP release from taste buds and GPCR-mediated taste perception. Thus, CALHM3, together with CALHM1, is essential to form the fast voltage-gated ATP-release channel in type II TBCs required for GPCR-mediated tastes. Ma et al. identify a CALHM1/CALHM3 hetero-hexameric ion channel as the mechanism by which type II taste bud cells release ATP as a neurotransmitter to gustatory neurons in response to GPCR-mediated tastes, including sweet, bitter, and umami substances. © 2018 Elsevier Inc.ATP releaseblue-native pageconcatemerhexamerknockoutmousepatch-clamp electrophysiologysingle-molecule photobleachingtaste budvoltage-gatedAnimalsCalcium ChannelsFemaleHEK293 CellsHeLa CellsHumansIon Channel GatingMiceMiceTransgenicReceptorsG-Protein-CoupledReceptorsPurinergicSynaptic TransmissionTasteTaste PerceptionXenopusadenosine triphosphatecalcium channelcalcium homeostasis modulator 1calcium homeostasis modulator 3G protein coupled receptorion channelpurinergic receptorunclassified drugvoltage gated calcium channelcalcium channelCALHM1 proteinmouseG protein coupled receptorpurinergic receptoraction potentialactivation constantadultanimal cellanimal experimentanimal modelanimal tissueArticlebitter tastecalcium homeostasisCALHM3 genecell activitychannel gatingcontrolled studyfemalegene deletiongene expressiongene interactiongene locationHEK293T cell lineHeLa cell linehumanhuman cellin vivo studyion currentmalemolecular interactionmouseNeuro-2a cell lineneurotransmissionnonhumanpriority journalsweetnesstastetaste bud cellumamianimalHEK293 cell linephysiologysynaptic transmissiontastetransgenic mouseXenopusDentistryOral Biology and Oral PathologyOther DentistryArticle