DARPP-32 is a protein typically associated with neurons bearing the D1-R (dopamine receptor of the D1 subtype) (Mayerhofer et al.,1999).
NCBI Summary:
Midbrain dopaminergic neurons play a critical role in multiple brain functions, and abnormal signaling through dopaminergic pathways has been implicated in several major neurologic and psychiatric disorders. One well-studied target for the actions of dopamine is DARPP32. In the densely dopamine- and glutamate-innervated rat caudate-putamen, DARPP32 is expressed in medium-sized spiny neurons (Ouimet and Greengard, 1990 [PubMed 2191086]) that also express dopamine D1 receptors (Walaas and Greengard, 1984 [PubMed 6319627]). The function of DARPP32 seems to be regulated by receptor stimulation. Both dopaminergic and glutamatergic (NMDA) receptor stimulation regulate the extent of DARPP32 phosphorylation, but in opposite directions (Halpain et al., 1990 [PubMed 2153935]). Dopamine D1 receptor stimulation enhances cAMP formation, resulting in the phosphorylation of DARPP32 (Walaas and Greengard, 1984 [PubMed 6319627]); phosphorylated DARPP32 is a potent protein phosphatase-1 (see MIM 176875) inhibitor (Hemmings et al., 1984 [PubMed 6087160]). NMDA receptor stimulation elevates intracellular calcium, which leads to activation of calcineurin and dephosphorylation of phospho-DARPP32, thereby reducing the phosphatase-1 inhibitory activity of DARPP32 (Halpain et al., 1990 [PubMed 2153935]).[supplied by OMIM]
General function
Comment
The product of the DARPP-32 gene mediates intracellular signals initiated by the binding of dopamine to its receptors (Zhou et al.,1999). Dopamine and dopamine D1 agonists convert DARPP-32, from its dephosphorylated, inactive form into its Thr34-phosphorylated, active form, and that these effects on DARPP-32 constitute essential components of the mechanism by which dopamine and D1 agonists achieve their biological effects; in contrast dopamine D2 agonists dephosphorylate and inactivate DARPP-32 (Nishi et al,1999). Reed et al. (1998) found that, in the mouse, PDEs (cyclic nucleotide phosphodiesterases) regulate the phosphorylation of DARPP32. Svennilson et al.(1999) found that, in the central nervous system, D1 receptors require the dopamine and cAMP-regulated DARPP-32 to mediate their actions; renal D1 mediates DARPP-32 activation via a cascade involving cAMP and PKA, and protein kinase C (PKC) activation via phospholipase C. Active DARPP-32 has a
specific inhibitory effect on protein phosphatase 1 (PP1), leaving, e.g. Na+,K+-ATPase in a phosphorylated, inactive, state.
Cellular localization
Comment
Ovarian function
Luteinization
Comment
The presence of dopamine (DA) and a functional DA receptor and DARPP-32 indicate that a novel, physiological regulatory pathway involving DA exists in the human ovary (Mayerhofer et al.,1999).
Expression regulated by
LH
Comment
Estradiol synthesis was not affected by the expression of Dopamine and cAMP-regulated phosphoprotein of DARPP-32 (Mayerhofer et al.,1999).
Ovarian localization
Granulosa, Luteal cells
Comment
In cultured granulosa cells, dopamine and SKF-38393 (a selective D1 agonist) induced increased threonine-phosphorylation of DARPP-32, even in the presence of propranolol but not in the presence of 1-R antagonist SCH-23390 (Mayerhofer et al.,1999).
Follicle stages
Preovulatory, Corpus luteum
Comment
Mayerhofer A, et al 2001 reported the role of D1-Receptor, DARPP-32, and PP-1 in the Primate Corpus Luteum and Luteinized Granulosa Cells and evidence for Phosphorylation of DARPP-32 by Dopamine and Human Chorionic Gonadotropin.The multifunctional phosphoprotein "dopamine and cAMP-related phosphoprotein, M(r) 32,000" (DARPP-32), which is able to act as an intracellular third messenger, was found to be present in human luteinized granulosa cells (GCs) and human ovary. DARPP-32 phosphorylation in GCs was increased by dopamine (DA) acting via a DA-1 receptors (D1-R).
Immunoprecipitation studies showed that hCG, as well as DA, increased phosphorylation of DARPP-32 at threonine residues within 10 min, indicating that the signal transduction pathways of a hormone and a neurotransmitter involve DARPP-32 in GC
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Ovarian Function and Morphology after Deletion of the DARPP-32 Gene in Mice.
Mayerhofer A, et al .
A plethora of systemic and local signaling molecules regulate ovarian function, but how different signaling molecules interact within an ovarian target cell is not known. Here we report that endocrine cells of the ovary express a phosphoprotein, DARPP-32 (dopamine and cyclic AMP-regulated phosphoprotein of Mr 32,000), which integrates signaling molecules in neurons. We thus hypothesized that DARPP-32 might act in a similar way in ovarian endocrine cells and therefore studied whether DARPP-32 gene deletion has consequences for ovarian functions in mice. Reproductive performance of adult mutants did not differ from wild-type females, as judged from numbers of litters and pups delivered. Similar steroid levels in mutant and wild-type mice ruled out gross abnormalities in the hypothalamic-pituitary-ovarian axis. However, an analysis of ovarian morphology, using serially sectioned ovaries, revealed several differences. Ovaries of young adult mutant mice at 2 - 3 months contained luteinized follicles, but fewer corpora lutea. At 5 - 6 months, large cysts were found in mutant mice, as well as reduced numbers of preantral follicles and antral follicles. Interstitial cell hypertrophy and degeneration was marked in all mutant ovaries at this age. Thus, while the lack of DARPP-32 does not overtly alter reproductive performance in adult mice, it is associated with progressive alterations and derangements of growth and development of ovarian follicles, suggesting premature ovarian ageing. This implies that ovarian DARPP-32 is involved in follicular development, presumably by integrating effects of signaling molecules, which act together to ensure efficient follicular development.
Species: mouse
Mutation name: DARPP-32 gene disruption
type: targeted overexpression fertility: unknown Comment: Levels of plasma adrenocorticotropin (ACTH) and corticosterone which reflect HPA
activity were measured in mice receiving cocaine injections. In wild-type controls, 'binge' cocaine administration significantly increased plasma
ACTH and corticosterone levels. In contrast, DARPP-32-deficient mice failed to show a significant elevation of either plasma ACTH or corticosterone levels following 'binge' cocaine. The results indicate that DARPP-32 plays a role in mediating the stimulatory effects of cocaine on the HPA axis (Zhou et al,1999). Hiroi et al.(1999) found that repeated cocaine administration increased levels of DeltaFosB, a Fos family transcription factor in the striatum of wild-type mice, and this increase was abolished in DARPP-32-mutant mice. Nishi et al. (1999) theorized that dopamine D2 agonists dephosphorylate and inactivate DARPP-32. They examined regulation of the activity of the electrogenic ion pump Na+,K+-ATPase, an established target for dopamine signalling and found that dopamine D1 agonists and dopamine D2 agonists inhibit Na+,K+-ATPase activity in dissociated cells from the mouse neostriatum and that, in each case, the effect was abolished in cells from mice deficient in DARPP-32. They concluded that DARPP-32 may play an obligatory role in dopaminergic signalling mediated both by D1 receptors and by D2 receptors.