Elevated intracellular calcium in transformed lymphoblasts in bipolar I disorder

dPK). a tetrameric protein composed of 2 regulatory and catalytic subunits, is the primary targetor intracellular cAMPsignalling, and the levels of some cAMP·dPK regulatory subunit isoforms may be moduluted by changes in cytosolic cAMP levels consequent 10 activation or receptors coupled to this second messenger, In the present study. we assessed whether[iH)cAMP binding. a measure of cAMP-dPK regulatory subunit levels. is altered in cortical regions of postmortem BDbrains in which higher GOl~ protein levels have been previously identified. eH)cAMPbinding measured in cytosolic and membrane fractions from postmortem temporal cortex by the procedure of (Takeda et nl,J Biochen: 105:327-329, 1989), was saturable and specific with Kd values of 0.89 ± 0.1 nM(sltc I) and 3.6 :!: 0.47 nM (:tile 2). and Brnax of 154 :!: 28,26 fmoVms r,rotein (site I) and 283 :t 36.49 fmoUmg prolein (sile 2). Specific [ HlcAMP (S nM)binding wasestimated both on cytosolic and membrane fractions from frontal, temporal, parietal, and occipital cortices.and cerebellum and thalamus of postmortem brain from 10 patients with BD compared with age and postmortem-delay matched controls, (JHleAMP binding was significantly reduced (-28%, p =: O.()4) in cytosollc fractions from BO temporal cortex compared "lith matched controls. A trendtoward decreased [;1H]cAMP binding was also observed in cytosolic fractions from frontal (-23%). parietal (-18%) and occipital (-26%) cortex, and cerebellum (-35%), but not in thalamus. In contrast, ['H!cAMP. binding was not slgniflcamly different between BD and control subjects in membrane fraeuons of theregions examined. Lithium levels measured in temporal cortex correlated slgnlficantly with 13HlcAMP binding in temporal cortex (r= 0.68,p=O.03) and cerebellum (r=0.86, p=0.02) of BO brain. These results suggest that decreased cytosolic cAMP-dPK levels found in postmortem BD brain may be a result of antemortem lithium andlor mood stabilizer treatment and may notreflect enhanced cAMP signnlJing per se, Supported by the MRC and Clarke Institute Research Foundation.