D1-Receptor, DARPP-32, and PP-1 in the Primate Corpus Luteum and Luteinized Granulosa Cells: Evidence for Phosphorylation of DARPP-32 by Dopamine and Human Chorionic Gonadotropin
Artur Mayerhofer,
Stephanie Fritz,
Robert Grünert,
Sheryl L. Sanders,
Diane M. Duffy,
Sergio R. Ojeda and
Richard L. Stouffer
Anatomisches Institut (A.M., S.F., R.G.), Universität
München, D-80802 München, Germany; and Oregon Regional
Primate Research Center-Oregon Health Sciences University, Divisions of
Reproductive Sciences (S.L.S., D.M.D., R.L.S.) and Neuroscience (A.M.,
S.R.O.), Beaverton, Oregon 97006
Address correspondence and requests for reprints to: Artur Mayerhofer, M.D., Professor of Molecular Anatomy, Anatomisches Institut, Universität München, Biedersteiner Str. 29, D-80802 München, Germany. E-mail: Mayerhofer{at}lrz.tum.de
The multifunctional phosphoprotein "dopamine and cAMP-related
phosphoprotein,Mr 32,000" (DARPP-32), which is able to
act as an intracellularthird messenger, was previously found to be
present in humanluteinized granulosa cells (GCs) and human ovary.
DARPP-32 phosphorylationin GCs was increased by dopamine (DA) acting
via a DA-1 receptors(D1-R). In the present study, we examined whether
the majorendocrine signaling molecule for GCs, LH/human CG (hCG),
couldalso affect DARPP-32 phosphorylation. Immunoprecipitation studies
showedthat hCG, as well as DA, increased phosphorylation of DARPP-32
atthreonine residues within 10 min, indicating that the signal
transductionpathways of a hormone and a neurotransmitter involve
DARPP-32in GCs. Phosphorylated DARPP-32 is known to inhibit a cellular
phosphatase(PP-1), which was also found to be expressed by GCs. Using
RT-PCRand sequence analyses we showed that DARPP-32, PP-1, and D1-R
geneswere not restricted to cultured luteinized GCs, but were
expressedin vivo, in the corpus luteum (CL) of the
rhesus monkey throughoutits entire life span. Whereas hCG increased
steroid productionin monkey luteinized GCs and in isolated luteal
cells, DA failedto affect basal or hCG-stimulated progesterone
production. Thisindicates that, unlike the LH/hCG receptor, the D1-R
is notdirectly linked to steroid production. Although the preciserole
of D1-R in the CL remains to be shown, the presence ofD1-R, DARPP-32,
and its target PP-1 in this endocrine tissue,as well as the
phosphorylation of DARPP-32 by a gonadotropinand by DA in luteinized
GCs, indicate that the signal transductionpathways of the
neurotransmitter DA and the gonadotropin hCG/LHinvolve DARPP-32. The
PP-1 inhibitor DARPP-32 may, thus, bea third messenger used by both DA
and hCG/LH to exert commonregulatory influences on the cells of the
CL.
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