From the Research
Relationship between Inositol Trisphosphate (IP3) and Lithium
- The relationship between IP3 and lithium is complex, with lithium affecting the phosphatidylinositol signaling system in two ways: depleting inositol and elevating inositol monophosphate levels followed by phosphoinositols accumulation 1.
- Lithium stimulates the accumulation of second-messenger IP3 and other inositol phosphates in mouse pancreatic minilobules without inositol supplementation 2.
- The inositol depletion hypothesis proposes that lithium's beneficial action in the treatment of bipolar disorder is attributable to its inhibition of the enzymatic breakdown of inositol phosphates to free inositol, resulting in a reduction in free intracellular inositol 3.
- IP3 accumulation and/or inositol depletion may mediate lithium's behavioral and cellular changes, with IP3 administration affecting bipolar-related behaviors and autophagy markers in a lithium-like manner 1.
- Lithium inhibits the final dephosphorylation step of the metabolic pathways that generate IP3, thus reducing the supply of free inositol required to maintain the lipid precursors used for signaling 4.
Effects of Lithium on IP3 and Inositol Phosphates
- Lithium increases the accumulation of IP3 and inositol 1,3,4,5-tetrakisphosphate in mouse pancreatic minilobules, followed by a decrease 2.
- Lithium impairs stimulated cyclic GMP production in both the cortex and hippocampus, and reduces pilocarpine-induced increases of IP3 in the cortex 5.
- The effects of lithium on the accumulation of other inositol phosphates parallel that of IP3, with the exception of inositol 3,4-bisphosphate, which decreases 2.
Mechanisms of Lithium's Action
- Lithium's inhibition of inositol monophosphatase may lead to the accumulation of IP3 and other inositol phosphates, which can mediate its therapeutic effects 3, 1.
- The inositol depletion hypothesis and the IP3 accumulation hypothesis are two alternative explanations for lithium's mechanism of action, with both hypotheses proposing that lithium's blockade of inositol phosphatase is the key event 3, 1.