Interaction of calbindin D28k and inositol monophosphatase in human postmortem cortex: possible implications for bipolar disorder.
OBJECTIVE
Therapeutically relevant concentrations of lithium (Li) exert an uncompetitive inhibition on inositol monophosphatase (IMPase). It has recently been shown that calbindin D28k (calbindin) activates IMPase. Purified calbindin attaches to a specific amino acid sequence on purified IMPase enhancing its activity by several hundred fold. We studied whether calbindin activates IMPase in postmortem human brain crude homogenate, whether differences in calbindin levels between lymphocytes and brain may be responsible for our previous finding of reduced IMPase activity in lymphocytes but not brain of bipolar patients, and whether calbindin protein levels are altered in postmortem brain from bipolar patients versus control subjects and schizophrenic and major depressive patients.


METHODS
IMPase activity in human postmortem brain specimens with or without 10 microM human recombinant calbindin was quantified spectrophotometrically in an enzyme-linked immunosorbent assay (ELISA) reader. Calbindin protein levels in postmortem brain were determined using Western blot analysis.


RESULTS
Supplementation of human recombinant calbindin to postmortem human brain crude homogenate enhanced IMPase activity by 3.5-fold. No difference in postmortem temporal cortex calbindin protein levels was found between bipolar patients versus comparison groups. Two-fold higher calbindin protein levels were found in Li-treated bipolar patients compared with other bipolar patients. Subchronic Li treatment in mice did not affect brain calbindin protein levels significantly. Chronic Li treatment reduced calbindin protein levels in the frontal cortex but not in the hippocampus.


CONCLUSIONS
Calbindin is a physiological activator of IMPase in human brain. Protein levels of calbindin are not altered in postmortem temporal cortex of bipolar patients.
Shamir
Alon
A
Stanley Foundation Research Center, Faculty of Health Sciences, Ben Gurion University of the Negev and Mental Health Center, Beer Sheva, Israel.
Elhadad
Naama
N
Belmaker
Robert H
RH
Agam
Galila
G
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D064092:Calbindin 1; D064026:Calbindins; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016651:Lithium Carbonate / Q000494:pharmacology / Q000627:therapeutic use; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism*
D014150:Antipsychotic Agents; C576498:CALB1 protein, human; C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D064030:S100 Calcium Binding Protein G; D016651:Lithium Carbonate; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase