Complex regulation of Cav2.2 N-type Ca2+ channels by Ca2+ and G-proteins.
G-protein coupled receptors inhibit Cav2.2 N-type Ca2+ channels by a fast, voltage-dependent pathway mediated by Gαi/Gβγ and a slow, voltage-independent pathway mediated by Gαq-dependent reductions in phosphatidylinositol 4,5-bisphosphate (PIP2) or increases in arachidonic acid. Studies of these for...
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Public Library of Science (PLoS)
2025-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0314839 |
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| author | Jessica R Thomas Jinglang Sun Juan De la Rosa Vazquez Amy Lee |
| author_facet | Jessica R Thomas Jinglang Sun Juan De la Rosa Vazquez Amy Lee |
| author_sort | Jessica R Thomas |
| collection | DOAJ |
| description | G-protein coupled receptors inhibit Cav2.2 N-type Ca2+ channels by a fast, voltage-dependent pathway mediated by Gαi/Gβγ and a slow, voltage-independent pathway mediated by Gαq-dependent reductions in phosphatidylinositol 4,5-bisphosphate (PIP2) or increases in arachidonic acid. Studies of these forms of regulation generally employ Ba2+ as the permeant ion, despite that Ca2+ -dependent pathways may impinge upon G-protein modulation. To address this possibility, we compared tonic G-protein inhibition of currents carried by Ba2+ (IBa) and Ca2+ (ICa) in HEK293T cells transfected with Cav2.2. Both IBa and ICa exhibited voltage-dependent facilitation (VDF), consistent with Gβγ unbinding from the channel. Compared to that for IBa, VDF of ICa was less sensitive to an inhibitor of Gα proteins (GDP-β-S) and an inhibitor of Gβγ (C-terminal construct of G-protein coupled receptor kinase 2). While insensitive to high intracellular Ca2+ buffering, VDF of ICa that remained in GDP-β-S was blunted by reductions in PIP2. We propose that when G-proteins are inhibited, Ca2+ influx through Cav2.2 promotes a form of VDF that involves PIP2. Our results highlight the complexity whereby Cav2.2 channels integrate G-protein signaling pathways, which may enrich the information encoding potential of chemical synapses in the nervous system. |
| format | Article |
| id | doaj-art-74e4a33752dc4a439ce02e38d6b99757 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-74e4a33752dc4a439ce02e38d6b997572025-02-12T05:31:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032025-01-01202e031483910.1371/journal.pone.0314839Complex regulation of Cav2.2 N-type Ca2+ channels by Ca2+ and G-proteins.Jessica R ThomasJinglang SunJuan De la Rosa VazquezAmy LeeG-protein coupled receptors inhibit Cav2.2 N-type Ca2+ channels by a fast, voltage-dependent pathway mediated by Gαi/Gβγ and a slow, voltage-independent pathway mediated by Gαq-dependent reductions in phosphatidylinositol 4,5-bisphosphate (PIP2) or increases in arachidonic acid. Studies of these forms of regulation generally employ Ba2+ as the permeant ion, despite that Ca2+ -dependent pathways may impinge upon G-protein modulation. To address this possibility, we compared tonic G-protein inhibition of currents carried by Ba2+ (IBa) and Ca2+ (ICa) in HEK293T cells transfected with Cav2.2. Both IBa and ICa exhibited voltage-dependent facilitation (VDF), consistent with Gβγ unbinding from the channel. Compared to that for IBa, VDF of ICa was less sensitive to an inhibitor of Gα proteins (GDP-β-S) and an inhibitor of Gβγ (C-terminal construct of G-protein coupled receptor kinase 2). While insensitive to high intracellular Ca2+ buffering, VDF of ICa that remained in GDP-β-S was blunted by reductions in PIP2. We propose that when G-proteins are inhibited, Ca2+ influx through Cav2.2 promotes a form of VDF that involves PIP2. Our results highlight the complexity whereby Cav2.2 channels integrate G-protein signaling pathways, which may enrich the information encoding potential of chemical synapses in the nervous system.https://doi.org/10.1371/journal.pone.0314839 |
| spellingShingle | Jessica R Thomas Jinglang Sun Juan De la Rosa Vazquez Amy Lee Complex regulation of Cav2.2 N-type Ca2+ channels by Ca2+ and G-proteins. PLoS ONE |
| title | Complex regulation of Cav2.2 N-type Ca2+ channels by Ca2+ and G-proteins. |
| title_full | Complex regulation of Cav2.2 N-type Ca2+ channels by Ca2+ and G-proteins. |
| title_fullStr | Complex regulation of Cav2.2 N-type Ca2+ channels by Ca2+ and G-proteins. |
| title_full_unstemmed | Complex regulation of Cav2.2 N-type Ca2+ channels by Ca2+ and G-proteins. |
| title_short | Complex regulation of Cav2.2 N-type Ca2+ channels by Ca2+ and G-proteins. |
| title_sort | complex regulation of cav2 2 n type ca2 channels by ca2 and g proteins |
| url | https://doi.org/10.1371/journal.pone.0314839 |
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