/myo-inositol transporter (HMIT) as a neuronal regulator of phosphoinositide signalling

6 Phosphoinositide signalling regulates a series of important neuronal processes that are thought to be altered in mood disorders. Furthermore, mood-stabilizing drugs inhibit key enzymes that regulate phosphoinositide production and alter neuronal growth cone morphology in an inositol-reversible manner. Because inositol is not synthesised in neurons these cells rely on its uptake from the extracellular fluid via transporters. We have investigated the expression and function of the H + /myo-inositol transporter (HMIT) as a potential regulator of inositol signalling in neurons and as a possible drug target for mood disorders. Using a specific anti-HMIT antibody, we have demonstrated that HMIT is primarily a neuronal transporter, widely expressed in the rat and human brain, with particularly high levels in the hippocampus and cortex where it is primarily located intracellularly. No HMIT-mediated electrophysiological responses were detected in rat brain neurons even after stimulation. Furthermore, we have generated an HMIT knockout mouse, which is viable. Using neurons dissected from E15 mouse cortex we have shown that inositol uptake is not altered in knockout neurons. Overall, these data do not support a role for HMIT as the neuronal plasma membrane inositol transporter. However, using an HMIT triple mutant that is expressed at the plasma membrane when transfected into HEK293 cells we have shown that HMIT can also transport IP 3 , therefore indicating possible intracellular functions in regulating neuronal activity that will be investigated using the knockout mice.