Figure 4. Increased extracellular, but not intracellular, dopamine levels confer hypersensitivity to Mn toxicity while decreased levels are protective. (A) Schematic representation of a generic dopaminergic synapse in C. elegans. (B) Total DA levels in selected mutants relevant to the study at the L1 larval stage.
dat-1(
ok157),
dop-2(
vs105);
dop-1(
vs100)
dop-3(
vs106) display significantly (p<0.001) higher dopamine levels than WT or other mutants, while dopamine measurement in
cat-2(
e1112) and
dat-1(
ok157);
cat-2(
e1112) did not reach a significant value compared to the background levels measured in our experiment. (C)
dat-1(
ok157) is hypersensitive (p<0.001) to Mn-induced lethality, with a LD50 = 9 mM.
cat-2(
e1112) is hyper-resistant (p<0.001) to Mn-induced lethality, with a LD50 = 95 mM.
cat-2(
e1112) rescues
dat-1(
ok157) hypersensitivity in the double-mutant
cat-2(
e1112);
dat-1(
ok157), which LD50 = 83 mM is not significantly different from
cat-2(
e1112) mutant. 10 mM DA pre-treatment restores Mn sensitivity (p<0.001) in both
cat-2(
e1112) and
cat-2(
e1112);
dat-1(
ok157), with respective LD50 of 34 mM and 40 mM. (D) The VMAT2 mutant
cat-1(
e1111) exhibits hyper-resistance to Mn (p<0.001), with a LD50 = 108 mM; while the DA receptor mutant
dop-2(
vs105);
dop-1(
vs100)
dop-3(
vs106) is hypersensitive to Mn exposure (p<0.001), with a LD50 = 27 mM.