Integrin receptor activation triggers converging regulation of Cav1.2 calcium channels by c-Src and protein kinase A pathways
Integrin receptor activation triggers converging regulation of Cav1.2 calcium channels by c-Src and protein kinase A pathways
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DOI：
10.1074/jbc.m600433200
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发表时间：
2006-05-19
影响因子：
4.8
通讯作者：
Davis, Michael J.
中科院分区：
文献类型：
--
作者：
Gui, Peichun;Wu, Xin;Davis, Michael J.
L-type, voltage-gated Ca2+ channels (CaL) play critical roles in brain and muscle cell excitability. Here we show that currents through heterologously expressed neuronal and smooth muscle CaL channel isoforms are acutely potentiated following alpha 5 beta 1 integrin activation. Only the alpha(1C) pore-forming channel subunit is critical for this process. Truncation and site-directed mutagenesis strategies reveal that regulation of Cav1.2 by alpha 5 beta 1 integrin requires phosphorylation of alpha(1C) C-terminal residues Ser(1901) and Tyr(2122). These sites are known to be phosphorylated by protein kinase A(PKA) and c-Src, respectively, and are conserved between rat neuronal (Cav1.2c) and smooth muscle (Cav1.2b) isoforms. Kinase assays are consistent with phosphorylation of these two residues by PKA and c-Src. Following alpha 5 beta 1 integrin activation, native CaL channels in rat arteriolar smooth muscle exhibit potentiation that is completely blocked by combined PKA and Src inhibition. Our results demonstrate that integrin-ECM interactions are a common mechanism for the acute regulation of CaL channels in brain and muscle. These findings are consistent with the growing recognition of the importance of integrin-channel interactions in cellular responses to injury and the acute control of synaptic and blood vessel function.
