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Journal of Neuroscience, Vol 14, 1251-1261, Copyright © 1994 by Society for Neuroscience
Expression of a calmodulin-dependent phosphodiesterase isoform (PDE1B1) correlates with brain regions having extensive dopaminergic innervation
JW Polli and RL Kincaid
Section on Immunology, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20852.
Cyclic nucleotide-dependent protein phosphorylation plays a central role in
neuronal signal transduction. Neurotransmitter-elicited increases in
cAMP/cGMP brought about by activation of adenylyl and guanylyl cyclases are
downregulated by multiple phosphodiesterase (PDE) enzymes. In brain, the
calmodulin (CaM)-dependent isozymes are the major degradative activities
and represent a unique point of intersection between the cyclic nucleotide-
and calcium (Ca2+)-mediated second messenger systems. Here we describe the
distribution of the PDE1B1 (63 kDa) CaM-dependent PDE in mouse brain. An
anti-peptide antiserum to this isoform immunoprecipitated approximately
30-40% of cytosolic PDE activity, whereas antiserum to PDE1A2 (61 kDa
isoform) removed 60-70%, demonstrating that these isoforms are the major
CaM- dependent PDEs in brain. Quantification of PDE1B1 immunoreactivity on
immunoblots indicated that striatum contains 3-17-fold higher levels of
PDE1B1 than other brain regions, with lowest immunoreactivity in
cerebellum. In situ hybridization demonstrated high levels of PDE1B1 mRNA
in the caudate-putamen, nucleus accumbens, and olfactory tubercle. Moderate
mRNA levels were observed in dentate gyrus, cerebral cortex, medial
thalamic nuclei, and brainstem, whereas negligible mRNA was detectable in
the globus pallidus, islands of Calleja, substantia nigra, and ventral
tegmental area. Immunocytochemistry confirmed that the majority of PDE1B1
protein was localized to the caudate-putamen, nucleus accumbens, and
olfactory tubercle. Within the caudate-putamen, PDE1B1 immunoreactivity was
ubiquitous, while PDE1A2 immunostaining was restricted to a minor subset of
striatal neurons. The expression of PDE1B1 protein and mRNA correlate
strongly with areas of the brain that are richest in dopaminergic
innervation; indeed, there are strikingly similar distributions for PDE1B1
and D1 dopamine receptor mRNAs. Since D1 receptor binding activates
adenylyl cyclase, and striatal neurons lack CaM-sensitive forms of cyclase,
the high amount of this PDE implies an important physiological role for
Ca(2+)-regulated attenuation of cAMP-dependent signaling pathways following
dopaminergic stimulation.
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