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Vol. 53, Issue 1, 23-32, January 1998
Division of Reproductive Biology, Department of Gynecology and
Obstetrics, Stanford University Medical Center, Stanford, California
94305-5317 (T.B., F.N., C.S., M.H., M.C.),
Institute of Histology and
General Embryology, University of Rome, La Sapienza, Rome 00161, Italy
(S.I., M.C.), and
Syntex Research, Palo Alto, California 94303 (E.R.S.)
To determine the properties of the cAMP-specific, rolipram-sensitive
phosphodiesterases (cAMP-PDEs) that are expressed in different organs,
monoclonal and polyclonal antibodies were raised against different
epitopes present in the cAMP-PDE sequences. Of the several antibodies
generated against peptides and fusion proteins, one monoclonal and four
polyclonal antibodies recognized both the native cAMP-PDEs as well as
the denatured proteins on Western immunoblot analysis. An
immunoprecipitation assay demonstrated that these antibodies recognized
the recombinant rat PDE4A, PDE4B, and PDE4D proteins with different
avidity. The polyclonal antibody K118 and the monoclonal M3S1 were most
specific for rat PDE4B and PDE4D forms, respectively, whereas the AC55
antiserum displayed the highest affinity for PDE4A forms. This
selectivity was confirmed by Western blot analysis using recombinant
rat PDE4A, PDE4B, and PDE4D proteins expressed in a heterologous
system. These antibodies were used to characterize the cAMP-PDEs
expressed in the rat brain. An immunoblot of extract of cortex and
cerebellum demonstrated that at least seven different polypeptides
specifically cross-reacted with the different antibodies, indicating
that multiple cAMP-PDEs are expressed in this tissue. On the basis of
cross-reactivity with PDE4D but not PDE4A or PDE4B antibodies, 93- and
105-kDa PDE4D species were detected in the cortex and cerebellum
extract. These forms are different from the 68-kDa PDE4D form expressed in endocrine cells after hormonal stimulation. Although the 93-kDa form
was recovered in both the soluble and particulate fractions, the
105-kDa polypeptide was mostly particulate in the cortex and cerebellum
extracts. PDE4B forms of 90-87 kDa were recovered in both soluble and
particulate compartments of the brain extract. These forms were
different from the previously identified PDE4A variants of 110 and 75 kDa. These data demonstrate that the presence of multiple cAMP-PDE
genes is translated into cAMP-PDE proteins of different sizes and
distinct immunological properties and that multiple variants derived
from these cAMP-PDE genes are expressed in different regions of the
brain and different subcellular compartments. These immunological tools
will be useful to identify different cAMP-PDE forms expressed in organs
targeted for pharmacological intervention with PDE4 inhibitors.
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