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Journal of Neuroscience, Vol 14, 973-984, Copyright © 1994 by Society for Neuroscience
Differential expression of the 61 kDa and 63 kDa calmodulin-dependent phosphodiesterases in the mouse brain
C Yan, JK Bentley, WK Sonnenburg and JA Beavo
Department of Pharmacology, University of Washington, Seattle 98195.
Based on their relative abundance and regulation by Ca2+ and by
phosphorylation in vitro, it is thought that the Ca2+/calmodulin- dependent
phosphodiesterases (CaM-PDEs) are important modulators of cyclic nucleotide
function in the brain. Two of the most abundant CaM- PDEs in the brain are
the 61 kDa and 63 kDa isozymes. In this study, the regional and cellular
expression of mRNA encoding these two different isoforms in mouse brain has
been determined by in situ hybridization. The 63 kDa CaM-PDE mRNA has a
wide-spread but uneven distribution. Very strong hybridization signals are
present in the caudate-putamen, nucleus accumbens, olfactory tubercle, and
dentate gyrus of the hippocampus. Somewhat lesser amounts of 63 kDa CaM-PDE
mRNA are present in the olfactory bulb and piriform cortex. Weaker but
still easily discernible hybridization signals are seen in several layers
of the cerebral cortex, CA1 and CA3 regions of the hippocampus, amygdaloid
nuclear complex, thalamus, hypothalamus, midbrain, brainstem, cerebellum,
and spinal cord. A weak hybridization signal was detected in the globus
pallidus of the basal ganglia. In general, the distribution of the 63 kDa
CaM-PDE is very similar to that of dopamine receptors, suggesting that it
may modulate dopamine function. In contrast, the 61 kDa CaM-PDE mRNA has a
more limited and much different distribution, with the highest level of
expression in the cerebral cortex and in the pyramidal cells of the
hippocampus. A moderate hybridization signal was detected in the medial
habenula and amygdaloid nuclear complex. In addition, small subsets of
neurons in several other regions showed specific hybridization. Both PDE
mRNAs appear to be localized exclusively in neuronal cell bodies. Their
distinct distribution suggests important but different physiological roles
for these two isozymes in the regional regulation of cyclic nucleotides in
the CNS. Since these two isozymes are differentially phosphorylated by
cAMP-dependent and Ca2+/CaM-dependent protein kinases, the differential
expression also provides a potential mechanism by which these PDEs can
differentially regulate cAMP and cGMP in different brain areas. The high
expression levels in specific subsets of neurons also suggest that agents
increasing Ca2+ in these neurons will increase the rate of cyclic
nucleotide degradation.
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