Membrane and Cell BiologyMembrane and Cell BiologyБиологические мембраны0233-47553034-5219The Russian Academy of Sciences66741810.31857/S0233475524050047cbwmefОБЗОРЫReview ArticleStructure and function of the proton channel OTOP1Структура и функции протонного канала OTOP1SladkovK. D.СладковК. Д.
Russian Federation
klimitrich@ya.ruKolesnikovS. S.КолесниковС. С.
Russian Federation
klimitrich@ya.ruInstitute of Cell Biophysics, Russian Academy of Sciences, FRC PSCBR RASИнститут биофизики клетки РАН, ФИЦ ПНЦБИ РАН04112024415-640041226022025Copyright ©; 2024, The Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024The Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0233-4755/article/view/667418

OTOP1 belongs to the otopetrin family of membrane proteins that form proton channels in cells of diverse types. In mammals, OTOP1 is involved in sour transduction in taste cells and contributes to otoconia formation in the inner ear. From the structural point of view, otopetrins, including OTOP1, represent a quasi-tetramer consisting of four α-barrels. The exact transport pathways mediating proton flux through the OTOP1 channel and gating units modulating its activity are still a matter of debate. This review discusses current data on structural and functional features of OTOP1. Suggested proton transport pathways, regulatory mechanisms, and key amino acid residues determining functionality of the otopetrins are considered. The existing kinetic models of OTOP1 are discussed as well. Based on revealed functional properties, OTOP1 is suggested to operate as a logical XOR element that allows for proton flux only if transmembrane pH gradient exists.

OTOP1 – мембранный белок, функционирующий как протонный канал в ряде тканей. В частности, OTOP1 вовлечен в трансдукцию кислых стимулов во вкусовых клетках млекопитающих. Структура белков семейства отопетринов представляет собой гомодимер из двух субъединиц, каждая из которых состоит из двух гомологичных α-бочек. В данном обзоре анализируется связь структуры и функции белка OTOP1, рассматриваются предполагаемые пути транспорта протона, а также обсуждаются механизмы модуляции протонного тока и существующие кинетические модели OTOP1. Имеющиеся данные позволяют рассматривать логический элемент исключающего ИЛИ (XOR) как функциональный эквивалент OTOP1, который обеспечивает поток протонов, только если значения рН по разные стороны мембраны различаются.

OTOP1otopetrinsproton channeltaste cellsOTOP1отопетриныпротонный каналвкусовые клеткиРоссийский научный фондRussian Science Foundation22-14-00032Whitten S.T., García-Moreno E.B., Hilser V.J. 2005. Local conformational fluctuations can modulate the coupling between proton binding and global structural transitions in proteins. Proc. Nat. Acad. Sci. USA. 102 (12), 4282–4287.Baca J.M., Ortega A.O., Jiménez A.A., Principal S.G. 2022. Cells electric charge analyses define specific properties for cancer cells activity. Bioelectrochem. 144, 108028.Soto E., Ortega-Ramírez A., Vega R. 2018. Protons as messengers of intercellular communication in the nervous system. Front. Cell. Neurosci. 12, 342.Pattison L.A., Callejo G., St John Smith E. 2019. Evolution of acid nociception: ion channels and receptors for detecting acid. Philos. Trans. R. Soc. B. 374 (1785), 20190291.Ruffin V.A., Salameh A.I., Boron W.F., Parker M.D. 2014. Intracellular pH regulation by acid-base transporters in mammalian neurons. Front. Physiol. 5, 74282.Decoursey T.E. 2003. Voltage-gated proton channels and other proton transfer pathways. Physiol. Rev. 83 (2), 475–579.DeCoursey T.E. 2018. Voltage and pH sensing by the voltage-gated proton channel, HV1. J. R. Soc. Interface. 15 (141), 20180108.Hurle B., Ignatova E., Massironi S.M., Mashimo T., Rios X., Thalmann I., Thalmann R., Ornitz D.M. 2003. Non-syndromic vestibular disorder with otoconial agenesis in tilted/mergulhador mice caused by mutations in otopetrin 1. Hum. Mol. Genet. 12 (7), 777–789.Tu Y.H., Cooper A.J., Teng B., Chang R.B., Artiga D.J., Turner H.N., Mulhall E.M., Ye W., Smith A.D., Liman E.R. 2018. An evolutionarily conserved gene family encodes proton-selective ion channels. Science. 359, 1047–1050.Hughes I., Saito M., Schlesinger P.H., Ornitz D.M. 2007. Otopetrin 1 activation by purinergic nucleotides regulates intracellular calcium. Proc. Nat. Acad. Sci. USA. 104 (29), 12023–12028.Kim S., Ahn H., Kim D., Cho S.W., Kim S. 2024. OTOP1: A new candidate gene for non-syndromic peg lateralis. Research Square. doi 10.21203/rs.3.rs-3811797/v1.Tu Y.H., Liu N., Xiao C., Gavrilova O., Reitman M.L. 2023. Loss of Otopetrin 1 affects thermoregulation during fasting in mice. Plos One. 18 (10), e0292610.Chang W.W., Matt A.S., Schewe M., Musinszki M., Grüssel S., Brandenburg J., Garfield D., Bleich M., Baukrowitz T., Hu M.Y. 2021. An otopetrin family proton channel promotes cellular acid efflux critical for biomineralization in a marine calcifier. Proc. Nat. Acad. Sci. USA. 118 (30), e2101378118.Liman E.R., Kinnamon S.C. 2021. Sour taste: Receptors, cells and circuits. Curr. Opin. Physiol. 20, 8–15.Li B., Wang Y., Castro A., Ng C., Wang Z., Chaudhry H., Agbaje Z., Ulloa G.A., Yu Y. 2022. The roles of two extracellular loops in proton sensing and permeation in human Otop1 proton channel. Commun. Biol. 5, 1110.Taruno A., Nomura K., Kusakizako T., Ma Z., Nureki O., Foskett J.K. 2021. Taste transduction and channel synapses in taste buds. Pflügers Arch. – Eur. J. Physiol. 473, 3–13.Yoshida R., Miyauchi A., Yasuo T., Jyotaki M., Murata Y., Yasumatsu K., Shigemura N., Yanagawa Y., Obata K., Ueno H., Margolskee R.F. 2009. Discrimination of taste qualities among mouse fungiform taste bud cells. J. Physiol. 587 (18), 4425–4439.Chang R.B., Waters H., Liman E.R. 2010. A proton current drives action potentials in genetically identified sour taste cells. Proc. Nat. Acad. Sci. USA. 107(51), 22320–22325.Teng B., Wilson C.E., Tu Y.H., Joshi N.R., Kinnamon S.C., Liman E.R. 2019. Cellular and neural responses to sour stimuli require the proton channel Otop1. Curr. Biol. 29 (21), 3647–3656.Liang Z., Wilson C.E., Teng B., Kinnamon S.C., Liman E.R. 2023. The proton channel OTOP1 is a sensor for the taste of ammonium chloride. Nat. Comm. 14 (1), 6194.Tian L., Zhang H., Yang S., Luo A., Kamau P.M., Hu J., Luo L., Lai R. 2023. Vertebrate OTOP1 is also an alkali-activated channel. Nat. Comm. 14 (1), 26.Sakmann B., Neher E. (ed.). 2009. Single-channel recording. 2nd ed. New York etc.: Springer-Science and Business Media. 700 p.Machtens J.-Ph., Fahlke C., Kovermann P. 2011. Noise analysis to study unitary properties of transporter-associated ion channels. Channels. 5 (6), 468–474.Teng B., Kaplan J.P., Liang Z., Chyung K.S., Goldschen-Ohm M.P., Liman E.R. 2023. Zinc activation of OTOP proton channels identifies structural elements of the gating apparatus. Elife. 12, e85317.Bushman J.D., Ye W., Liman E.R. 2015. A proton current associated with sour taste: Distribution and functional properties. FASEB J. 29, 3014–3026.Hughes M.P. 2024. The cellular zeta potential: cell electrophysiology beyond the membrane. Integr. Biol. 16, 1–11.Teng B., Kaplan J.P., Liang Z., Krieger Z., Tu Y.H., Burendei B., Ward A.B., Liman E.R. 2022. Structural motifs for subtype-specific pH-sensitive gating of vertebrate otopetrin proton channels. eLife. 11, 77946.Hille B. 1992. Ionic channels of excitable membranes. 2nd ed. Sunderland: Sinauer Associates, Inc. 607 p.Ohtubo Y. 2021. Slow recovery from the inactivation of voltage-gated sodium channel Nav1.3 in mouse taste receptor cells. Pflügers Archiv – Eur. J. Physiol. 473 (6), 953–968.Saotome K., Teng B., Tsui C.C., Lee W.H., Tu Y.H., Kaplan J.P., Sansom M.S.P., Liman E.R., Ward A.B. 2019. Structures of the otopetrin proton channels Otop1 and Otop3. Nat. Struct. Mol. Biol. 26, 518–525.Chen Q., Zeng W., She J., Bai X.C., Jiang Y. 2019. Structural and functional characterization of an otopetrin family proton channel. Elife. 8, e46710.Delemotte L. 2019. Outlining the proton-conduction pathway in otopetrin channels. Nat. Struct. Mol. Biol. 26 (7), 528–530.Kratochvil H.T., Watkins L.C., Mravic M., Thomaston J.L., Nicoludis J.M., Somberg N.H., Liu L., Hong M., Voth G.A., DeGrado W.F. 2023. Transient water wires mediate selective proton transport in designed channel proteins. Nat. Chem. 15 (7), 1012–1021.Levitz J., Royal P., Comoglio Y., Wdziekonski B., Schaub S., Clemens D.M., Isacoff E.Y., Sandoz G. 2016. Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels. Proc. Nat. Acad. Sci. USA. 113 (15), 4194–4199.Islam M.M., Sasaki O., Yano-Nashimoto S., Okamatsu-Ogura Y., Yamaguchi S. 2023. Cibacron blue 3G-A is a novel inhibitor of Otopetrin 1 (OTOP1), a proton channel. Biochem. Biophys. Res. Comm. 665, 64–70.Kim E., Hyrc K.L., Speck J., Salles F.T., Lundberg Y.W., Goldberg M.P., Kachar B., Warchol M.E., Ornitz D.M. 2011. Missense mutations in Otopetrin 1 affect subcellular localization and inhibition of purinergic signaling in vestibular supporting cells. Mol. Cell. Neurosci. 46 (3), 655–661.Kariev A.M., Green M.E. 2019. Quantum calculation of proton and other charge transfer steps in voltage sensing in the Kv1.2 channel. The Journal of Physical Chemistry B, 123 (38), 7984–7998.Weiner I.D., Verlander J.W. 2017. Ammonia transporters and their role in acid-base balance. Physiol. Rev. 97 (2), 465–494.Richards T.W. 2002. The relation of the taste of acids to their degree of dissociation. J. Phys. Chem. 4 (3), 207–211.Сладков К.Д., Колесников С.С. 2023. Модель молекулярного сенсора протона. Биол. мембраны. 40 (3), 188–193.Graham I., Duke T. 2005. The logical repertoire of ligand-binding proteins. Phys. Biol. 2 (3), 159.