Neuronal Reprograming of Protein Homeostasis by Calcium-Dependent Regulation of the Heat Shock Response
Figure 4
Modulation of AChR and GABAR can restore post-synaptic folding.
(A) At the C. elegans NMJ, the functional balance between GABAR and AChR signaling regulates post-synaptic muscle function. (B) L-AChR activation with the agonist levamisole (in water) suppressed Q35 aggregation at 5 µM, but enhanced aggregation at 50 µM. Mutant AChR unc-38(e264) is a control for AChR-mediated effect. (C) Reduction in GABAR function with lindane (in 10% EtOH) suppressed Q35 aggregation at 25 µM, and enhanced aggregation at 1 mM concentration (relative to EtOH control treatment). (D) Effect on Q35 aggregation by decrease in GABA with unc-49 or unc-47 RNAi, and by inhibition of GABA in unc-47(gk192) or unc-30(e191) mutant backgrounds. (E) Incubation with 50–200 mM GABA (in water) suppressed Q35 aggregation. GABA at 50 mM abolished the suppressor effect of gei-11, by “re-balancing” the GABAergic-cholinergic signaling. (F) Real-time qPCR analysis of hsp-70 (C12C8.1, F44E5.4) levels in 5 day old wt animals upon treatment with ACh, levamisole or the GABAR antagonist Lindane, or upon decrease in GABAergic signaling by either RNAi or mutant backgrounds of unc-47(gk192), unc-49(e407) or unc-30(e191). Student t-test **p<0.01 and ***p<0.001; data and statistics are relative to Q35;vector control (±SD) (RNAi controls: Table S1).