The β-cell primary cilium is an autonomous Ca2+ compartment for paracrine GABA signaling
The primary cilium is an organelle present in most adult mammalian cells that is considered as an antenna for sensing the local microenvironment. Here, we use intact mouse pancreatic islets of Langerhans to investigate signaling properties of the primary cilium in insulin-secreting β-cells. We find...
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| Veröffentlicht in: | The Journal of cell biology 2023-01, Vol.222 (1), p.1 |
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| creator | Sanchez, Gonzalo Manuel Incedal, Tugce Ceren Prada, Juan O'Callaghan, Paul Dyachok, Oleg Echeverry, Santiago Dumral, Özge Nguyen, Phuoc My Xie, Beichen Barg, Sebastian Kreuger, Johan Dandekar, Thomas Idevall-Hagren, Olof |
| description | The primary cilium is an organelle present in most adult mammalian cells that is considered as an antenna for sensing the local microenvironment. Here, we use intact mouse pancreatic islets of Langerhans to investigate signaling properties of the primary cilium in insulin-secreting β-cells. We find that GABAB1 receptors are strongly enriched at the base of the cilium, but are mobilized to more distal locations upon agonist binding. Using cilia-targeted Ca2+ indicators, we find that activation of GABAB1 receptors induces selective Ca2+ influx into primary cilia through a mechanism that requires voltage-dependent Ca2+ channel activation. Islet β-cells utilize cytosolic Ca2+ increases as the main trigger for insulin secretion, yet we find that increases in cytosolic Ca2+ fail to propagate into the cilium, and that this isolation is largely due to enhanced Ca2+ extrusion in the cilium. Our work reveals local GABA action on primary cilia that involves Ca2+ influx and depends on restricted Ca2+ diffusion between the cilium and cytosol. |
| doi_str_mv | 10.1083/jcb.202108101 |
| format | Article |
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Here, we use intact mouse pancreatic islets of Langerhans to investigate signaling properties of the primary cilium in insulin-secreting β-cells. We find that GABAB1 receptors are strongly enriched at the base of the cilium, but are mobilized to more distal locations upon agonist binding. Using cilia-targeted Ca2+ indicators, we find that activation of GABAB1 receptors induces selective Ca2+ influx into primary cilia through a mechanism that requires voltage-dependent Ca2+ channel activation. Islet β-cells utilize cytosolic Ca2+ increases as the main trigger for insulin secretion, yet we find that increases in cytosolic Ca2+ fail to propagate into the cilium, and that this isolation is largely due to enhanced Ca2+ extrusion in the cilium. Our work reveals local GABA action on primary cilia that involves Ca2+ influx and depends on restricted Ca2+ diffusion between the cilium and cytosol.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.202108101</identifier><identifier>PMID: 36350286</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Animals ; Beta cells ; Calcium - metabolism ; Calcium channels (voltage-gated) ; Calcium influx ; Calcium ions ; Calcium sequestration ; Cell activation ; Cell Signaling ; Cells, Cultured ; Cilia ; Cilia - metabolism ; Cytosol ; gamma-Aminobutyric Acid - metabolism ; Glucose - metabolism ; Insulin ; Insulin - metabolism ; Insulin secretion ; Islets of Langerhans ; Islets of Langerhans - metabolism ; Mammalian cells ; Mice ; Microenvironments ; Paracrine signalling ; Physiology ; Receptors ; Receptors, GABA-B - metabolism ; Signaling ; γ-Aminobutyric acid</subject><ispartof>The Journal of cell biology, 2023-01, Vol.222 (1), p.1</ispartof><rights>2022 Sanchez et al.</rights><rights>Copyright Rockefeller University Press Jan 2023</rights><rights>2022 Sanchez et al. 2022 Sanchez et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c345t-59035f236a38e17b4763267a702edb069a7caa78f9393920cd7aab9629082ea93</citedby><cites>FETCH-LOGICAL-c345t-59035f236a38e17b4763267a702edb069a7caa78f9393920cd7aab9629082ea93</cites><orcidid>0000-0003-1825-9793 ; 0000-0003-4415-1866 ; 0000-0003-1396-571X ; 0000-0003-4661-5724 ; 0000-0002-0241-6304 ; 0000-0003-3117-5367 ; 0000-0003-4155-7457 ; 0000-0001-7145-9802 ; 0000-0003-1886-7625</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36350286$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sanchez, Gonzalo Manuel</creatorcontrib><creatorcontrib>Incedal, Tugce Ceren</creatorcontrib><creatorcontrib>Prada, Juan</creatorcontrib><creatorcontrib>O'Callaghan, Paul</creatorcontrib><creatorcontrib>Dyachok, Oleg</creatorcontrib><creatorcontrib>Echeverry, Santiago</creatorcontrib><creatorcontrib>Dumral, Özge</creatorcontrib><creatorcontrib>Nguyen, Phuoc My</creatorcontrib><creatorcontrib>Xie, Beichen</creatorcontrib><creatorcontrib>Barg, Sebastian</creatorcontrib><creatorcontrib>Kreuger, Johan</creatorcontrib><creatorcontrib>Dandekar, Thomas</creatorcontrib><creatorcontrib>Idevall-Hagren, Olof</creatorcontrib><title>The β-cell primary cilium is an autonomous Ca2+ compartment for paracrine GABA signaling</title><title>The Journal of cell biology</title><addtitle>J Cell Biol</addtitle><description>The primary cilium is an organelle present in most adult mammalian cells that is considered as an antenna for sensing the local microenvironment. Here, we use intact mouse pancreatic islets of Langerhans to investigate signaling properties of the primary cilium in insulin-secreting β-cells. We find that GABAB1 receptors are strongly enriched at the base of the cilium, but are mobilized to more distal locations upon agonist binding. Using cilia-targeted Ca2+ indicators, we find that activation of GABAB1 receptors induces selective Ca2+ influx into primary cilia through a mechanism that requires voltage-dependent Ca2+ channel activation. Islet β-cells utilize cytosolic Ca2+ increases as the main trigger for insulin secretion, yet we find that increases in cytosolic Ca2+ fail to propagate into the cilium, and that this isolation is largely due to enhanced Ca2+ extrusion in the cilium. Our work reveals local GABA action on primary cilia that involves Ca2+ influx and depends on restricted Ca2+ diffusion between the cilium and cytosol.</description><subject>Animals</subject><subject>Beta cells</subject><subject>Calcium - metabolism</subject><subject>Calcium channels (voltage-gated)</subject><subject>Calcium influx</subject><subject>Calcium ions</subject><subject>Calcium sequestration</subject><subject>Cell activation</subject><subject>Cell Signaling</subject><subject>Cells, Cultured</subject><subject>Cilia</subject><subject>Cilia - metabolism</subject><subject>Cytosol</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>Glucose - metabolism</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin secretion</subject><subject>Islets of Langerhans</subject><subject>Islets of Langerhans - metabolism</subject><subject>Mammalian cells</subject><subject>Mice</subject><subject>Microenvironments</subject><subject>Paracrine signalling</subject><subject>Physiology</subject><subject>Receptors</subject><subject>Receptors, GABA-B - metabolism</subject><subject>Signaling</subject><subject>γ-Aminobutyric acid</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc-KFDEQxoMo7rh69CoBL4L0Wkm68-cijIOuCwte1oOnUJ1Jz2bo7oxJt-Br-SA-06bZcXCXHCpV-fFRXz5CXjO4YKDFh71rLzjwcmfAnpAVa2qoNKvhKVlBmVem4c0ZeZHzHgBqVYvn5ExI0QDXckV-3Nx6-vdP5Xzf00MKA6bf1IU-zAMNmeJIcZ7iGIc4Z7pB_p66OBwwTYMfJ9rFREuDLoXR08v1pzXNYTdiH8bdS_Kswz77V8d6Tr5_-Xyz-Vpdf7u82qyvKyfqZqoaA6LpuJAotGeqrZUUXCpUwP22BWlQOUSlOyPK4eC2CrE1khvQ3KMR5-Tjve5hbge_dWWvhL09erERg334MoZbu4u_rNFMGA1F4N1RIMWfs8-THUJe_gNHX1xbrkQtGTdsQd8-QvdxTsXvQknQWkqzUNU95VLMOfnutAwDu4RmS2j2FFrh3_zv4ET_S0ncAU30khY</recordid><startdate>20230102</startdate><enddate>20230102</enddate><creator>Sanchez, Gonzalo Manuel</creator><creator>Incedal, Tugce Ceren</creator><creator>Prada, Juan</creator><creator>O'Callaghan, Paul</creator><creator>Dyachok, Oleg</creator><creator>Echeverry, Santiago</creator><creator>Dumral, Özge</creator><creator>Nguyen, Phuoc My</creator><creator>Xie, Beichen</creator><creator>Barg, Sebastian</creator><creator>Kreuger, Johan</creator><creator>Dandekar, Thomas</creator><creator>Idevall-Hagren, Olof</creator><general>Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1825-9793</orcidid><orcidid>https://orcid.org/0000-0003-4415-1866</orcidid><orcidid>https://orcid.org/0000-0003-1396-571X</orcidid><orcidid>https://orcid.org/0000-0003-4661-5724</orcidid><orcidid>https://orcid.org/0000-0002-0241-6304</orcidid><orcidid>https://orcid.org/0000-0003-3117-5367</orcidid><orcidid>https://orcid.org/0000-0003-4155-7457</orcidid><orcidid>https://orcid.org/0000-0001-7145-9802</orcidid><orcidid>https://orcid.org/0000-0003-1886-7625</orcidid></search><sort><creationdate>20230102</creationdate><title>The β-cell primary cilium is an autonomous Ca2+ compartment for paracrine GABA signaling</title><author>Sanchez, Gonzalo Manuel ; 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Here, we use intact mouse pancreatic islets of Langerhans to investigate signaling properties of the primary cilium in insulin-secreting β-cells. We find that GABAB1 receptors are strongly enriched at the base of the cilium, but are mobilized to more distal locations upon agonist binding. Using cilia-targeted Ca2+ indicators, we find that activation of GABAB1 receptors induces selective Ca2+ influx into primary cilia through a mechanism that requires voltage-dependent Ca2+ channel activation. Islet β-cells utilize cytosolic Ca2+ increases as the main trigger for insulin secretion, yet we find that increases in cytosolic Ca2+ fail to propagate into the cilium, and that this isolation is largely due to enhanced Ca2+ extrusion in the cilium. Our work reveals local GABA action on primary cilia that involves Ca2+ influx and depends on restricted Ca2+ diffusion between the cilium and cytosol.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>36350286</pmid><doi>10.1083/jcb.202108101</doi><orcidid>https://orcid.org/0000-0003-1825-9793</orcidid><orcidid>https://orcid.org/0000-0003-4415-1866</orcidid><orcidid>https://orcid.org/0000-0003-1396-571X</orcidid><orcidid>https://orcid.org/0000-0003-4661-5724</orcidid><orcidid>https://orcid.org/0000-0002-0241-6304</orcidid><orcidid>https://orcid.org/0000-0003-3117-5367</orcidid><orcidid>https://orcid.org/0000-0003-4155-7457</orcidid><orcidid>https://orcid.org/0000-0001-7145-9802</orcidid><orcidid>https://orcid.org/0000-0003-1886-7625</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of cell biology, 2023-01, Vol.222 (1), p.1 |
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| subjects | Animals Beta cells Calcium - metabolism Calcium channels (voltage-gated) Calcium influx Calcium ions Calcium sequestration Cell activation Cell Signaling Cells, Cultured Cilia Cilia - metabolism Cytosol gamma-Aminobutyric Acid - metabolism Glucose - metabolism Insulin Insulin - metabolism Insulin secretion Islets of Langerhans Islets of Langerhans - metabolism Mammalian cells Mice Microenvironments Paracrine signalling Physiology Receptors Receptors, GABA-B - metabolism Signaling γ-Aminobutyric acid |
| title | The β-cell primary cilium is an autonomous Ca2+ compartment for paracrine GABA signaling |
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