{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T04:30:41Z","timestamp":1778905841803,"version":"3.51.4"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T00:00:00Z","timestamp":1633392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> The carotid body (CB) plays a critical role in oxygen sensing; however, the role of glutamatergic signaling in the CB response to hypoxia remains uncertain. We previously found that functional multiple glutamate transporters and inotropic glutamate receptors (iGluRs) are expressed in the CB. The aim of this present research is to investigate the expression of group I metabotropic glutamate receptors (mGluRs) (mGluR1 and 5) in the CB and its physiological function in rat CB response to acute hypoxia.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> RT-PCR and immunostaining were conducted to examine the mRNA and protein expression of group I mGluRs in the human and rat CB. Immunofluorescence staining was performed to examine the cellular localization of mGluR1 in the rat CB. <jats:italic>In vitro<\/jats:italic> carotid sinus nerve (CSN) discharge recording was performed to detect the physiological function of mGluR1 in CB response to acute hypoxia.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> We found that (1) mRNAs of mGluR1 and 5 were both expressed in the human and rat CB. (2) mGluR1 protein rather than mGluR5 protein was present in rat CB. (3) mGluR1 was distributed in type I cells of rat CB. (4) Activation of mGluR1 inhibited the hypoxia-induced enhancement of CSN activity (CSNA), as well as prolonged the latency time of CB response to hypoxia. (5) The inhibitory effect of mGluR1 activation on rat CB response to hypoxia could be blocked by GABA<jats:sub><jats:italic>B<\/jats:italic><\/jats:sub> receptor antagonist.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Our findings reveal that mGluR1 in CB plays a presynaptic feedback inhibition on rat CB response to hypoxia.<\/jats:p>","DOI":"10.3389\/fnins.2021.741214","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T14:22:49Z","timestamp":1633530169000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Metabotropic Glutamate Receptors 1 Regulates Rat Carotid Body Response to Acute Hypoxia via Presynaptic Mechanism"],"prefix":"10.3389","volume":"15","author":[{"given":"Chaohong","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baosheng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenlu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuzhen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/s0304-3940(00)00896-x","article-title":"Adenosine triphosphate-induced peripheral nerve discharges generated from the cat petrosal ganglion in vitro.","volume":"282","author":"Alcayaga","year":"2000","journal-title":"Neurosci. Lett."},{"key":"B2","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.brainres.2006.11.012","article-title":"ATP- and ACh-induced responses in isolated cat petrosal ganglion neurons.","volume":"1131","author":"Alcayaga","year":"2007","journal-title":"Brain Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"6012","DOI":"10.3390\/ijms21176012","article-title":"G-protein-coupled receptor (GPCR) signaling in the carotid body: roles in hypoxia and cardiovascular and respiratory disease.","volume":"21","author":"Aldossary","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.neuropharm.2009.01.002","article-title":"Metabotropic glutamate receptor-dependent long-term potentiation.","volume":"56","author":"Anwyl","year":"2009","journal-title":"Neuropharmacology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1159\/000075310","article-title":"Translational activity of N-methyl-D-aspartate receptor subunit NR1 mRNA in PC12 cells.","volume":"12","author":"Awobuluyi","year":"2003","journal-title":"Neurosignals"},{"key":"B6","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1038\/nature15721","article-title":"Oxygen regulation of breathing through an olfactory receptor activated by lactate.","volume":"527","author":"Chang","year":"2015","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"438","DOI":"10.4103\/1673-5374.266047","article-title":"Glutamate receptors and glutamatergic signalling in the peripheral nerves.","volume":"15","author":"Chen","year":"2020","journal-title":"Neural Regen. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/0304-3940(91)90729-d","article-title":"Expression of messenger RNAs for peptides and tyrosine hydroxylase in primary sensory neurons that innervate arterial baroreceptors and chemoreceptors.","volume":"129","author":"Czyzyk-Krzeska","year":"1991","journal-title":"Neurosci. Lett."},{"key":"B9","doi-asserted-by":"publisher","first-page":"13571","DOI":"10.1038\/ncomms13571","article-title":"Transduction of group I mGluR-mediated synaptic plasticity by beta-arrestin2 signalling.","volume":"7","author":"Eng","year":"2016","journal-title":"Nat. Commun."},{"key":"B10","doi-asserted-by":"publisher","first-page":"6885","DOI":"10.1523\/JNEUROSCI.22-16-06885.2002","article-title":"Modulation of presynaptic calcium transients by metabotropic glutamate receptor activation: a differential role in acute depression of synaptic transmission and long-term depression.","volume":"22","author":"Faas","year":"2002","journal-title":"J. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"401","DOI":"10.3389\/fphys.2020.00401","article-title":"Characterization of group I metabotropic glutamate receptors in rat and human adrenal glands.","volume":"11","author":"Fan","year":"2020","journal-title":"Front. Physiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1113\/jphysiol.2003.048298","article-title":"GABA mediates autoreceptor feedback inhibition in the rat carotid body via presynaptic GABAB receptors and TASK-1.","volume":"553","author":"Fearon","year":"2003","journal-title":"J. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/0306-4522(92)90534-9","article-title":"Transmitter diversity in carotid body afferent neurons: dopaminergic and peptidergic phenotypes.","volume":"51","author":"Finley","year":"1992","journal-title":"Neuroscience"},{"key":"B14","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1111\/j.1469-7793.2001.00421.x","article-title":"A characterisation of long-term depression induced by metabotropic glutamate receptor activation in the rat hippocampus in vitro.","volume":"537","author":"Fitzjohn","year":"2001","journal-title":"J. Physiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.resp.2018.08.007","article-title":"Acute oxygen sensing-role of metabolic specifications in peripheral chemoreceptor cells.","volume":"265","author":"Gao","year":"2019","journal-title":"Respir. Physiol. Neurobiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.neuropharm.2016.01.036","article-title":"Activation of mGluR1 contributes to neuronal hyperexcitability in the rat anterior cingulate cortex via inhibition of HCN channels.","volume":"105","author":"Gao","year":"2016","journal-title":"Neuropharmacology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"6879","DOI":"10.1523\/JNEUROSCI.15-10-06879.1995","article-title":"Multiple presynaptic metabotropic glutamate receptors modulate excitatory and inhibitory synaptic transmission in hippocampal area CA1.","volume":"15","author":"Gereau","year":"1995","journal-title":"J. Neurosci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1515\/revneuro-2017-0087","article-title":"G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication.","volume":"29","author":"Guidolin","year":"2018","journal-title":"Rev. Neurosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"53","DOI":"10.3389\/fendo.2019.00053","article-title":"Receptor-receptor interactions as a widespread phenomenon: novel targets for drug development?","volume":"10","author":"Guidolin","year":"2019","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.resp.2006.12.006","article-title":"Electrical and pharmacological properties of petrosal ganglion neurons that innervate the carotid body.","volume":"157","author":"Iturriaga","year":"2007","journal-title":"Respir. Physiol. Neurobiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.resp.2004.10.002","article-title":"Modulation of the hypoxic sensory response of the carotid body by 5-hydroxytryptamine: role of the 5-HT2 receptor.","volume":"145","author":"Jacono","year":"2005","journal-title":"Respir. Physiol. Neurobiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1093\/cercor\/bhx005","article-title":"mGluR2 versus mGluR3 metabotropic glutamate receptors in primate dorsolateral prefrontal cortex: postsynaptic mGluR3 strengthen working memory networks.","volume":"28","author":"Jin","year":"2018","journal-title":"Cereb. Cortex"},{"key":"B23","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1152\/japplphysiol.00726.2003","article-title":"Acetylcholine release from the carotid body by hypoxia: evidence for the involvement of autoinhibitory receptors.","volume":"96","author":"Kim","year":"2004","journal-title":"J. Appl. Physiol. (1985)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.neuropharm.2010.12.015","article-title":"Short- and long-term depression at glutamatergic synapses on hippocampal interneurons by group I mGluR activation.","volume":"60","author":"Le Duigou","year":"2011","journal-title":"Neuropharmacology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1186\/s12931-020-01468-z","article-title":"Functional glutamate transporters are expressed in the carotid chemoreceptor.","volume":"21","author":"Li","year":"2020","journal-title":"Respir. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1152\/japplphysiol.90626.2008","article-title":"Exposure to cyclic intermittent hypoxia increases expression of functional NMDA receptors in the rat carotid body.","volume":"106","author":"Liu","year":"2009","journal-title":"J. Appl. Physiol. (1985)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.neuroscience.2018.04.032","article-title":"AMPA receptor-dependent glutamatergic signaling is present in the carotid chemoreceptor.","volume":"382","author":"Liu","year":"2018","journal-title":"Neuroscience"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2518","DOI":"10.1111\/j.1460-9568.1995.tb01051.x","article-title":"Metabotropic glutamate receptors inhibiting excitatory synapses in the CA1 area of rat hippocampus.","volume":"7","author":"Manzoni","year":"1995","journal-title":"Eur. J. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/s0006-8993(00)02396-9","article-title":"Hypoxic modulation of L-type Ca(2+) channels in inspiratory brainstem neurones: intracellular signalling pathways and metabotropic glutamate receptors.","volume":"869","author":"Mironov","year":"2000","journal-title":"Brain Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1146\/annurev.pharmtox.011008.145533","article-title":"Metabotropic glutamate receptors: physiology, pharmacology, and disease.","volume":"50","author":"Niswender","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1515\/znc-2002-3-425","article-title":"A novel binding assay for metabotropic glutamate receptors using [3H] L-quisqualic acid and recombinant receptors.","volume":"57","author":"Ohashi","year":"2002","journal-title":"Z. Naturforsch. C J. Biosci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1146\/annurev-physiol-020518-114427","article-title":"Physiology of the carotid body: from molecules to disease.","volume":"82","author":"Ortega-S\u00e1enz","year":"2020","journal-title":"Annu. Rev. Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.cell.2013.12.013","article-title":"An O2-sensitive glomus cell-stem cell synapse induces carotid body growth in chronic hypoxia.","volume":"156","author":"Platero-Luengo","year":"2014","journal-title":"Cell"},{"key":"B34","doi-asserted-by":"publisher","first-page":"697","DOI":"10.3389\/fphys.2018.00697","article-title":"Receptor\u2013receptor interactions of G protein-coupled receptors in the carotid body: a working hypothesis.","volume":"9","author":"Porzionato","year":"2018","journal-title":"Front. Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1111\/j.1469-7793.2001.00667.x","article-title":"Expression of P2X2 and P2X3 receptor subunits in rat carotid body afferent neurones: role in chemosensory signalling.","volume":"537","author":"Prasad","year":"2001","journal-title":"J. Physiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1016\/j.neuron.2018.05.018","article-title":"Glutamatergic signaling in the central nervous system: ionotropic and metabotropic receptors in concert.","volume":"98","author":"Reiner","year":"2018","journal-title":"Neuron"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1038\/emboj.2009.177","article-title":"Crosstalk between GABAB and mGlu1a receptors reveals new insight into GPCR signal integration.","volume":"28","author":"Rives","year":"2009","journal-title":"EMBO J."},{"key":"B38","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/cne.903550310","article-title":"Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain.","volume":"355","author":"Romano","year":"1995","journal-title":"J. Comp. Neurol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"11315","DOI":"10.1523\/JNEUROSCI.23-36-11315.2003","article-title":"Pivotal role of nucleotide P2X2 receptor subunit of the ATP-gated ion channel mediating ventilatory responses to hypoxia.","volume":"23","author":"Rong","year":"2003","journal-title":"J. Neurosci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"4991","DOI":"10.1113\/JP274179","article-title":"Contribution of adenosine and ATP to the carotid body chemosensory activity in ageing.","volume":"597","author":"Sacramento","year":"2019","journal-title":"J. Physiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.neuropharm.2016.08.028","article-title":"A slow excitatory postsynaptic current mediated by a novel metabotropic glutamate receptor in CA1 pyramidal neurons.","volume":"115","author":"Sheng","year":"2017","journal-title":"Neuropharmacology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"7503","DOI":"10.1523\/JNEUROSCI.17-19-07503.1997","article-title":"Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus.","volume":"17","author":"Shigemoto","year":"1997","journal-title":"J. Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/j.neuroscience.2004.06.068","article-title":"Identification of M1 and M2 muscarinic acetylcholine receptors in the cat carotid body chemosensory system.","volume":"128","author":"Shirahata","year":"2004","journal-title":"Neuroscience"},{"key":"B44","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/s0165-3806(98)00152-7","article-title":"Changes in mRNA levels for group I metabotropic glutamate receptors following in utero hypoxia-ischemia.","volume":"112","author":"Simonyi","year":"1999","journal-title":"Brain Res. Dev. Brain Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1016\/s0028-3908(01)00005-3","article-title":"mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C.","volume":"40","author":"Skeberdis","year":"2001","journal-title":"Neuropharmacology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1098\/rspb.1993.0117","article-title":"Presynaptic inhibitory action of a metabotropic glutamate receptor agonist on excitatory transmission in visual cortical neurons.","volume":"253","author":"Sladeczek","year":"1993","journal-title":"Proc. Biol. Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/0197-0186(95)00130-1","article-title":"Glutamate in the glomus cells of the cat carotid body: immunocytochemistry and in vitro release.","volume":"28","author":"Torrealba","year":"1996","journal-title":"Neurochem. Int."},{"key":"B48","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1124\/pr.109.002451","article-title":"Glutamate receptor ion channels: structure, regulation, and function.","volume":"62","author":"Traynelis","year":"2010","journal-title":"Pharmacol. Rev."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.2174\/092986712799462702","article-title":"Assessing glutamatergic function and dysfunction in peripheral tissues.","volume":"19","author":"Tremolizzo","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1139\/y2012-054","article-title":"Autocrine and paracrine actions of ATP in rat carotid body.","volume":"90","author":"Tse","year":"2012","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/s0006-8993(03)03366-3","article-title":"ACh and ATP mediate excitatory transmission in cat carotid identified chemoreceptor units in vitro.","volume":"988","author":"Varas","year":"2003","journal-title":"Brain Res."},{"key":"B52","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1007\/s11064-020-03191-z","article-title":"Prenatal hypoxia induces premature aging accompanied by impaired function of the glutamatergic system in rat hippocampus.","volume":"46","author":"Vetrovoy","year":"2021","journal-title":"Neurochem. Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1038\/sj.bjp.0705570","article-title":"Presynaptic group I metabotropic glutamate receptors modulate synaptic transmission in the rat superior colliculus via 4-AP sensitive K(+) channels.","volume":"140","author":"White","year":"2003","journal-title":"Br. J. Pharmacol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/s0306-4522(01)00254-8","article-title":"Activation of metabotropic glutamate receptor 1 inhibits glutamatergic transmission in the substantia nigra pars reticulata.","volume":"105","author":"Wittmann","year":"2001","journal-title":"Neuroscience"},{"key":"B55","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3389\/fphar.2014.00012","article-title":"Complex GABAB receptor complexes: how to generate multiple functionally distinct units from a single receptor.","volume":"5","author":"Xu","year":"2014","journal-title":"Front. Pharmacol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1111\/j.1471-4159.2004.02978.x","article-title":"ATP inhibits the hypoxia response in type I cells of rat carotid bodies.","volume":"92","author":"Xu","year":"2005","journal-title":"J. Neurochem."},{"key":"B57","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1007\/s00441-014-1921-x","article-title":"Vesicular glutamate transporter 2-immunoreactive afferent nerve terminals in the carotid body of the rat.","volume":"358","author":"Yokoyama","year":"2014","journal-title":"Cell Tissue Res."},{"key":"B58","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1113\/jphysiol.2008.165035","article-title":"Postsynaptic action of GABA in modulating sensory transmission in co-cultures of rat carotid body via GABA(A) receptors.","volume":"587","author":"Zhang","year":"2009","journal-title":"J. Physiol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"3101","DOI":"10.1113\/JP274743","article-title":"Adenosine and dopamine oppositely modulate a hyperpolarization-activated current I(h) in chemosensory neurons of the rat carotid body in co-culture.","volume":"596","author":"Zhang","year":"2018","journal-title":"J. Physiol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1111\/j.1469-7793.2000.t01-1-00143.x","article-title":"Co-release of ATP and ACh mediates hypoxic signalling at rat carotid body chemoreceptors.","volume":"525","author":"Zhang","year":"2000","journal-title":"J. Physiol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1007\/s00702-014-1180-8","article-title":"Glutamate as a neurotransmitter in the healthy brain.","volume":"121","author":"Zhou","year":"2014","journal-title":"J. Neural Transm. (Vienna)"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.741214\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T14:22:52Z","timestamp":1633530172000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.741214\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,5]]},"references-count":61,"alternative-id":["10.3389\/fnins.2021.741214"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2021.741214","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,5]]},"article-number":"741214"}}