Figure 1.

Unfolded protein response to intermittent hypoxia, modeling sleep apnea. A, Schematic reveals the general response to unfolded proteins in mammalian cells, including neurons. BiP holds three sensor proteins in an inactive state in the membrane of the ER. In response to improperly folded proteins within the ER lumen, BiP is released from one or more of the three sensors, PERK, IRE1, and ATF6. Release from BiP promotes activation, phosphorylation of PERK and IRE1 (p-PERK and IRE1), and transfer of ATF6 to the Golgi where it is cleaved, before nuclear translocation. All three sensors can activate protective responses to ER stress, including selective translational attenuation and transcriptional upregulation to improve oxidative stress, reduce folding burden, and clear improperly folded proteins from the cell. All three sensors can promote the transcription of CHOP/GADD153, a proapoptotic protein. B, Conditions of short-term intermittent hypoxia (short IH, 3 d) resulted in increased PERK phosphorylation without an IH effect on the other two sensor proteins. Shown in the histograms are average ± SE band densities, with representative hypoglossal control (C) and short IH bands shown above. *p < 0.05.