Lithium, an inhibitor of cAMP-induced inositol 1,4,5-trisphosphate accumulation in Dictyostelium discoideum, inhibits activation of guanine-nucleotide-binding regulatory proteins, reduces activation of adenylylcyclase, but potentiates activation of guanylyl cyclase by cAMP.
Li+ drastically alters pattern formation in Dictyostelium by inhibiting cAMP-induced prespore-gene expression and promoting cAMP-induced prestalk-gene expression. We reported previously that Li+ inhibits inositol monophosphatases in this organism and strongly reduces basal and cAMP-stimulated inositol 1,4,5-trisphosphate levels. We show here that Li+ also reduces cAMP-induced accumulation of cAMP, but promotes cAMP-induced accumulation of cGMP. This effect is not due to inhibition of cGMP hydrolysis or inhibition of adaptation and may therefore reflect stimulation of guanylyl-cyclase activation. Li+ does not affect the binding of cAMP to surface receptors but interferes with the interaction between receptors and guanine-nucleotide-binding regulatory (G) proteins. These effects are complex; in the absence of Mg2+, Li+ increases guanosine 5'-[gamma-thio]triphosphate(GTP[S])-binding activity to similar levels as 1 mM Mg2+. However, while Mg2+ potentiates cAMP-induced stimulation of GTP[S]-binding activity, Li+ effectively inhibits stimulation. Li+ also inhibits cAMP-stimulated, but not basal high-affinity GTP-ase activity, indicating an inhibitory effect on cAMP-induced activation of G-proteins. Our data suggest that in addition to inositolphosphate metabolism, the activation of G-proteins may be a second biochemical target for Li+ effects on pattern formation and signal transduction in Dictyostelium.
Department of Biology, University of Leiden, The Netherlands.
D J
DJ
Peters
B E
BE
Snaar-Jagalska
P J
PJ
Van Haastert
P
P
Schaap
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004023:Dictyostelium / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology*; D015290:Second Messenger Systems / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015544:Inositol 1,4,5-Trisphosphate; D008094:Lithium; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase; D006152:Cyclic GMP