The high affinity inositol transport system--implications for the pathophysiology and treatment of bipolar disorder.
The 'inositol-depletion hypothesis' postulates that the therapeutic effects of lithium are due to inhibition of inositol monophosphatase, which leads to depletion of brain cells of myo-inositol and consequently to dampening of phosphoinositide (PI) signaling. This article examines the potential relevance of an alternative mechanism for inositol depletion: inhibition of myo-inositol uptake that proceeds via the sodium/myo-inositol cotransport (SMIT). We discuss recent in vitro experiments that show a pronounced downregulation of SMIT after chronic treatment with lithium, carbamazepine, and valproate at therapeutically relevant concentrations. It is concluded that downregulation of SMIT could represent a common mechanism of action of mood stabilizers.
Department of Psychiatry, University of Freiburg, Germany. calker@psyallg.ukl.uni-freiburg.de
D
D
van Calker
R H
RH
Belmaker
D018692:Antimanic Agents / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D002220:Carbamazepine / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007294:Inositol / Q000172:deficiency / Q000378:metabolism*; D018020:Lithium Compounds / Q000494:pharmacology*; D008565:Membrane Proteins; D027981:Symporters; D014635:Valproic Acid / Q000494:pharmacology
D018692:Antimanic Agents; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D018020:Lithium Compounds; D008565:Membrane Proteins; D027981:Symporters; C073884:SLC5A3 protein, human; D002220:Carbamazepine; D007294:Inositol; D014635:Valproic Acid