Synaptic defects and compensatory regulation of inositol metabolism in inositol polyphosphate 1-phosphatase mutants.
Phosphoinositides function as important second messengers in a wide range of cellular processes. Inositol polyphosphate 1-phosphatase (IPP) is an enzyme essential for the hydrolysis of the 1-phosphate from either Ins(1,4)P2 or Ins(1,3,4)P3. This enzyme is Li+ sensitive, and is one of the proposed targets of Li+ therapy in manic-depressive illness. Drosophila ipp mutants accumulate IP2 in their system and are incapable of metabolizing exogenous Ins(1,4)P2. Notably, ipp mutants demonstrate compensatory upregulation of an alternative branch in the inositol-phosphate metabolism tree, thus providing a means of ensuring continued availability of inositol. We demonstrate that ipp mutants have a defect in synaptic transmission resulting from a dramatic increase in the probability of vesicle release at larval neuromuscular junctions. We also show that Li+ phenocopies this effect in wild-type synapses. Together, these results support a role for phosphoinositides in synaptic vesicle function in vivo and mechanistically question the "lithium hypothesis."
Acharya
J K
JK
Howard Hughes Medical Institute, and Department of Biology, University of California, San Diego, La Jolla 92093, USA.
Labarca
P
P
Delgado
R
R
Jalink
K
K
Zuker
C S
CS
D000818:Animals; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004330:Drosophila / Q000201:enzymology / Q000235:genetics*; D004594:Electrophysiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D007295:Inositol Phosphates / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D018377:Neurotransmitter Agents / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism
D007295:Inositol Phosphates; D018377:Neurotransmitter Agents; C044259:inositol 1,4-bis(phosphate); C058097:inositol 1,3,4-trisphosphate; D008094:Lithium; D010744:Phosphoric Monoester Hydrolases; C053087:inositol-1,4-bisphosphate 1-phosphatase