Integrin receptor activation triggers converging regulation of Cav1.2 calcium channels by c-Src and protein kinase A pathways.
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 alpha5beta1 integrin activation. Only the alpha1C pore-forming channel subunit is critical for this process. Truncation and site-directed mutagenesis strategies reveal that regulation of Cav1.2 by alpha5beta1 integrin requires phosphorylation of alpha1C C-terminal residues Ser1901 and Tyr2122. 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 alpha5beta1 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.
Department of Medical Pharmacology & Physiology, University of Missouri School of Medicine, Columbia, Missouri 65212, USA.
Peichun
P
Gui
Xin
X
Wu
Shizhang
S
Ling
Stephanie C
SC
Stotz
Robert J
RJ
Winkfein
Emily
E
Wilson
George E
GE
Davis
Andrew P
AP
Braun
Gerald W
GW
Zamponi
Michael J
MJ
Davis
D000818:Animals; D001921:Brain / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D019061:src-Family Kinases
D020746:Calcium Channels, L-Type; D039081:Integrin alpha5beta1; C419385:L-type calcium channel alpha(1C); D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases