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EGFR (small dots) and IP3R1 (large dots) colocalize at PM–ER junctions.3 A, }1 ~" h- @% f& u$ A. g b
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On page 657, Hur et al. show that signaling complexes on the plasma membrane and ER, and two different signals, unite to coordinate calcium release.Many signaling pathways, sometimes in specific combinations, lead to calcium release from internal ER stores. In adrenal chromaffin cells, EGF alone does not cause store release unless the cells are first stimulated with bradykinin (BK), which is an inflammation-generated hormone.3 M: o" u) e P" j+ a! d
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Hur and colleagues show that this sensitized release requires BK's known ability to activate PKA. PKA was found in a large complex that linked the plasma membrane and the ER. The complex also included the EGF receptor (on the plasma membrane), the calcium-release channel IP3R1 (which was found in the ER), and a tethering protein called AKAP9.
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The binding of EGF to its receptor generates IP3 to open IP3R1, but this depends on prior phosphorylation of the receptor and IP3R1 in response to BK. IP3R1 was phosphorylated by BK-activated PKA, and the timing of this modification correlated with the window of time in which EGF caused calcium release. The existence of the complex does not depend on BK〞it was also found in unstimulated cells〞but it was required for EGF-induced calcium release. Proximity of the BK and EGF pathways thus imparts the specificity.6 m e% h% x+ g- z. O9 O u' E' B8 R
7 t! `( K. P* ]4 fBK alone also causes calcium store release, which in chromaffin cells triggers the exocytosis of neurohormones that stimulate heart rate and energy production. On its own, BK results in only transient neurohormone release. But by sensitizing cells to EGF, which can easily be taken up from the bloodstream, BK can produce a more lasting release. EGF does not need BK to cause calcium release in other cell types. The physiological relevance of the BK dependence in adrenal cells is unclear.(EGFR (small dots) and IP3R1 (large dots)) |
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发表于 2009-3-6 08:54
发表于 2015-6-16 09:34
