Increased Cyclic AMP-Dependent Protein Kinase Activity in
Postmortem Brain from Patients with Bipolar Affective Disorder
Anat Fields, Peter P. Li, Stephen J. Kish, and Jerry J. Warsh
Section of Biochemical Psychiatry, Centre for Addiction and Mental Health–Clarke Division; and Departments of Psychiatry and
Pharmacology and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
Abstract: Previous observations of reduced [3H]cyclic
AMP binding in postmortem brain regions from bipolar
affective disorder subjects imply cyclic AMP-dependent
protein kinase function may be altered in this illness. To
test this hypothesis, basal and stimulated cyclic AMP-
dependent protein kinase activity was determined in cy-
tosolic and particulate fractions of postmortem brain
from bipolar disorder patients and matched controls.
Maximal enzyme activity was significantly higher (104%)
in temporal cortex cytosolic fractions from bipolar disor-
der brain compared with matched controls. In temporal
cortex particulate fractions and in the cytosolic and par-
ticulate fractions of other brain regions, smaller but sta-
tistically nonsignificant increments in maximal enzyme
activity were detected. Basal cyclic AMP-dependent pro-
tein kinase activity was also significantly higher (40%) in
temporal cortex cytosolic fractions of bipolar disorder
brain compared with controls. Estimated EC50values for
cyclic AMP activation of this kinase were significantly
lower (70 and 58%, respectively) in both cytosolic and
particulate fractions of temporal cortex from bipolar dis-
order subjects compared with controls. These findings
suggest that higher cyclic AMP-dependent protein kinase
activity in bipolar disorder brain may be associated with a
reduction of regulatory subunits of this enzyme, reflecting
a possible adaptive response of this transducing enzyme
to increased cyclic AMP signaling in this disorder. Key
Words: Bipolar disorder—Cyclic AMP—Cyclic AMP-
dependent protein kinase—Postmortem brain.
J. Neurochem. 73, 1704–1710 (1999).
The pathophysiology of bipolar affective disorder
(BD) has been linked to disturbances in several second
messenger systems (Young et al., 1993; Dubovsky et al.,
1994; Perez et al., 1995; Jope et al., 1996; Emamghore-
ishi et al., 1997; Rahman et al., 1997; Shimon et al.,
1997). Substantial evidence suggests that altered guanine
nucleotide binding protein (G protein)-mediated cyclic
AMP signaling may play an important role in the devel-
opment of BD (reviewed by Manji, 1992; Hudson et al.,
1993). In this regard, recent work from this laboratory
has demonstrated elevated immunolabeling of the stim-
ulatory G protein ? subunit, Gs?, and associated eleva-
tions in forskolin-stimulated cyclic AMP formation in
the temporal and occipital cortex of postmortem brain
from BD patients as compared with matched controls
(Young et al., 1993).
The physiological effects of cyclic AMP are mediated
by the phosphorylation of specific proteins via the acti-
vation of cyclic AMP-dependent protein kinase (PKA).
The inactive PKA tetramer is composed of two catalytic
subunits (C subunits) and a dimer of regulatory subunits
(R subunits) (Taylor et al., 1990). Multiple isoforms of
both R (RI?, RI?, RII?, and RII?) and C (C?, C?, and
C?) subunits have been identified (Tasken et al., 1997).
Binding of cyclic AMP to each R subunit of the PKA
holoenzyme results in the release of two monomeric C
subunits from the dimer of the regulatory subunits. The
free C subunits then phosphorylate protein substrates
until the level of cyclic AMP diminishes, and the R
subunits regain their high affinity to C, reforming the
holoenzyme (reviewed by Taylor et al., 1990). Most cells
synthesize sufficient numbers of R subunits to maintain
the free C subunits at low levels in the basal state.
However, compensatory mechanisms that lead to altered
PKA activity and subunit abundance are displayed in
cells that are exposed to elevated cyclic AMP levels for
sustained intervals (reviewed by Spaulding, 1993). At
least part of this regulation of PKA by cyclic AMP
occurs through processes that directly alter PKA concen-
tration via transcriptional or posttranscriptional changes
in the production or degradation of the PKA subunits
(reviewed by Spaulding, 1993).
Direct evidence for the involvement of PKA in the
pathophysiology of BD has only recently been reported
and includes findings from this laboratory of reduced
binding of [3H]cyclic AMP in the cytosolic fraction of
postmortem brain regions from BD subjects compared
Received March 12, 1999; revised manuscript received June 17,
1999; accepted June 18, 1999.
Address correspondence and reprint requests to Dr. J. J. Warsh at
Section of Biochemical Psychiatry, Centre for Addiction and Mental
Health, 250 College Street, Toronto, ON, Canada M5T 1R8.
Abbreviations used: BD, bipolar affective disorder; C subunit, cat-
alytic subunit; G protein, guanine nucleotide binding protein; PKA,
cyclic AMP-dependent protein kinase; R subunit, regulatory subunit.
Journal of Neurochemistry
Lippincott Williams & Wilkins, Inc., Philadelphia
© 1999 International Society for Neurochemistry
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