Lithium inhibitable enzymes in postmortem brain of bipolar patients Galila Agam a,c, *, Galit Shatiel a,c , Nitsan Kozlovsky a , Hady Shimon b , R.H. Belmaker a,b a Stanley Research Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheva, Israel b Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheva, Israel c Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheva, Israel Received 22 July 2002; received in revised form 20 January 2003; accepted 29 January 2003 Abstract Despite considerable ongoing efforts at the epidemiological, genetic and molecular level, the etiology of bipolar disorder had not yetbeenelucidated.Tostudypossiblecontributingcomponentstothepathophysiologyofthisdisorder,wehavehypothesizedthat levels of enzymes inhibited by therapeutically relevent lithium ion concentrations in the brain of patients may differ from those in normal controls and may be involved in the etiology of the disorder. Three Li-inhibitable enzymes were studied in postmortem brainsamplesofbipolarpatientsandnormalcontrols.Theexpressionandfunctionofthetwoenzymesthatareobviouslyinvolved insignalingcascades,IMPase,involvedinthesecondmessengersystemofthephosphatidylinositolcycle,andGSK-3,amediatorof an array of signaling cascades, were not found to be different in postmortem frontal and occipital cortex of bipolar patients and normal controls. Only PAP phosphatase protein levels, but not its mRNA levels or enzymatic activity, were foudn to be sig- nificantly decreased in frontal cortex of bipolar patients compared with normal controls. # 2003 Elsevier Ltd. All rights reserved. Keywords: Postmortem brain; Bipolar disorder; Lithium; Inositol monophasphatase (IMPas); Glycogen synthase kinase (GSK)-3; Phosphoadeno- sine-phosphate (PAP) phosphatase 1. Introduction Despite intensive research efforts at the epidemiologi- cal, genetic and molecular level in the past decades, the etiology of bipolar disorder has not yet been elucidated. To study possible contributing components to the pathophysiology of this disorder, we have hypothesized that levels of enzymes inhibited by therapeutically rele- vant lithium ion concentrations in the brain of patients may differ from those in normal controls and may be involved in the etiology of the disorder. In the present study we summarize results of levels of three lithium (Li)-inhibitable enzymes in postmortem brain samples of bipolar patients and normal controls. The enzymes studied are inositol monophosphatase (IMPase), glyco- gen synthase kinase (GSK)-3 and phosphoadenosine- phosphate (PAP) phosphatase. 2. Inositol monophosphatase 2.1. Background Inositol monophosphatase (IMPase) is a key enzyme in brain signal transduction and is inhibited by lithium (Li) at therapeutic concentrations (Hallcher & Sherman 1980). Mammalian IMPase exists as a homodimer with subunit molecular weight of 30 kDa. The enzyme has three motifs (A, B and C), which contain most of the keyaminoacidsinvolvedinsubstrateandmetalbinding (Atack et al., 1995). Because Li inhibits IMPase with a Ki of 0.8 mM (Hallcher & Sherman 1980), enzymatic activity in fron- tal and occipital cortex was studied in two separate brain collections for possible overactivity in manic- depressive illness (Berridge et al., 1989). 0022-3956/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0022-3956(03)00044-X Journal of Psychiatric Research 37 (2003) 433–442 www.elsevier.com/locate/jpsychires * Corresponding author. Present address: Psychiatry Research Unit,MentalofHealthCenter,POBox4600,Beersheva84170,Israel. Fax: +972-7-6400737. E-mail address: agamg@netvision.net.il (G. Agam).