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Region-Specific Regulation of RGS4 (Regulator of G-Protein–Signaling

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Region-Specific Regulation of RGS4 (Regulator of G-Protein–Signaling The Journal of Neuroscience, May 15, 1999, 19(10):3674–3680 Region-Specific Regulation of RGS4 (Regulator of G-Protein–Signaling Protein Type 4) in Brain by Stress and Glucocorticoids: In Vivo and In Vitro Studies Yan G. Ni, Stephen J. Gold, Philip A. Iredale, Rose Z. Terwilliger, Ronald S. Duman, and Eric J. Nestler Laboratory of Molecular Psychiatry and Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06508 The present study demonstrates that the regulator of G-pro- analog dexamethasone. Consistent with the findings in vivo, tein–signaling protein type 4 (RGS4) is differentially regulated in dexamethasone treatment caused a dose- and time-dependent the locus coeruleus (LC) and the paraventricular nucleus (PVN) decrease in RGS4 mRNA levels in AtT20 cells but a dose- and of the hypothalamus by chronic stress and glucocorticoid treat- time-dependent increase in CATH.a cells. RGS4 mRNA regula- ments. Acute or chronic administration of corticosterone to tion seen in these two cell lines seems to be attributable, at adult rats decreased RGS4 mRNA levels in the PVN but in- least in part, to opposite changes in mRNA stability. The differ- creased these levels in the LC. Similarly, chronic unpredictable ential regulation of RGS4 expression in the LC and in key relays stress decreased RGS4 mRNA levels in the PVN but had a of the hypothalamic–pituitary–adrenal axis could contribute to strong trend to increase these levels in the LC. Chronic stress the brain’s region-specific and long-term adaptations to stress. also decreased RGS4 mRNA levels in the pituitary. The molec- Key words: RGS proteins; glucocorticoids; chronic stress; ular mechanisms of RGS4 mRNA regulation were further inves- locus coeruleus; paraventricular nucleus of the hypothalamus; tigated in vitro in the LC-like CATH.a cell line and the neuroen- HPA (hypothalamic–pituitary–adrenal) axis; CATH.a cells; AtT20 docrine AtT20 cell line using the synthetic corticosterone cells; cAMP pathway The recently discovered regulators of G-protein–signaling encoding RGS3–RGS11 in rat brain (Gold et al., 1997). Of these (RGS) proteins negatively modulate G-protein function by accel- RGS proteins, RGS4 mRNA is relatively abundant in many brain erating the GTPase activity of G-protein a subunits. There has regions, including several structures of the stress response cir- been intense interest in the function of RGS proteins, in partic- cuitry, such as the cerebral cortex, amygdala, thalamus, paraven- ular, in their interaction with G-proteins. Several members of the tricular nucleus (PVN) of the hypothalamus, and locus coeruleus RGS family inhibit Gai, Gao, Gaq, Gaz, or transducin (Gat) (LC). Although a recent study has shown changes in several RGS subunits but not GasorGa12 (Berman et al., 1996; Hunt et al., mRNAs after acute amphetamine treatment (Burchett et al., 1996; Watson et al., 1996; Hepler et al., 1997; Wieland et al., 1998), overall, little is known regarding the physiological conse- 1997). Because of its apparently exclusive expression in brain, quences of altered RGS protein expression. RGS protein type 4 (RGS4) has received a wealth of attention. One functional consequence of RGS4 regulation could be Experiments with purified recombinant proteins in vitro and with modulation of signaling via the cAMP pathway. Thus, a decrease stably transfected mammalian cells show that RGS4 attenuates in RGS4 expression, by enhancing Gai-mediated signaling, could Gai- and Gaq-mediated signaling by acting as a GTPase- result in diminished adenylyl cyclase activity. There is strong activating protein (Hepler et al., 1997; Huang et al., 1997). On the evidence that regulation of the cAMP pathway plays an impor- 2 basis of the crystal structure of RGS4 bound to AlF4 -activated tant role in stress responses. For instance, corticotropin-releasing Gai, it has been suggested that RGS4 accelerates the GTPase factor (CRF), the primary neurotransmitter controlling activity of activity of Gai and Gaq by stabilizing the a subunit’s transition the hypothalamic–pituitary–adrenal (HPA) axis, acts by stimu- state for GTP hydrolysis (Tesmer et al., 1997). lating adenylyl cyclase (Labrie et al., 1982; Litvin et al., 1984; We have characterized previously the distribution of mRNAs Battaglia et al., 1987). Adrenal glucocorticoid, a key hormone of the stress response, exerts negative feedback control over the HPA axis by inhibiting CRF secretion by the PVN and adreno- Received Nov. 3, 1998; revised Feb. 1, 1999; accepted Feb. 10, 1999. This work was supported by grants from the National Institute of Mental Health corticotropic hormone (ACTH) secretion by the pituitary. These and the National Institute on Drug Abuse and by the Abraham Ribicoff Research actions oppose the cAMP pathway, which is known to promote Facilities of the Connecticut Mental Health Center, State of Connecticut Depart- the synthesis and release of CRF and of ACTH in these tissues ment of Mental Health and Addiction Services. We wish to thank Dr. J. P. Herman for suggestions on the pituitary in situ hybridization experiments, Dr. Y. Lee for (Giguere et al., 1982; Labrie et al., 1982; Keller and Dallman, helpful discussions throughout the course of this study, Dr. M. Charlton for pro- 1984; Litvin et al., 1984; Dorin et al., 1993). In contrast, chronic viding U373 astrocytoma cell mRNA, and Ms. J. J. Spencer for technical help with stress induces upregulation of several components of the cAMP the chronic unpredictable stress experiments. Correspondence should be addressed to Dr. Eric J. Nestler, Department of pathway, including protein kinase A and adenylyl cyclase, in the Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT LC (Melia et al., 1992), a brain region thought to mediate certain 06508. Dr. Iredale’s present address: Central Research Division, Pfizer, Eastern Point attentional and autonomic features of the stress response. Road, Groton, CT 06340. The goal of the present study was to investigate directly the Copyright © 1999 Society for Neuroscience 0270-6474/99/193674-07$05.00/0 effect of chronic stress and corticosterone treatments on RGS4 Ni et al. • Regulation of RGS4 by Chronic Stress and Glucocorticoids J. Neurosci., May 15, 1999, 19(10):3674–3680 3675 expression in brain regions associated with the stress response cpm/ml (cyclophilin) 32P-labeled riboprobes. Blots were washed at 65°C 3 and to gain insight into the possible mechanisms involved by for 20 min in the following buffers: twice in 2 SSC and 0.1% SDS, once in 0.53 SSC and 0.1% SDS, and once in 0.13 SSC and 0.1% SDS. The analyzing RGS4 expression in two cell lines in vitro. We show that blots were visualized and quantified by image analysis (Molecular Im- chronic stress or glucocorticoid treatment decreases RGS4 ager System GS-363; Bio-Rad, Hercules, CA). RGS4 mRNA levels were mRNA levels in the PVN and pituitary but increases RGS4 normalized to cyclophilin levels to control for variations in gel loading mRNA levels in the LC. Decreased RGS4 expression in the PVN and RNA transfer. and pituitary, by potentiating Gai function, could contribute to In situ hybridization. In situ hybridization of brain sections was con- ducted either on free-floating sections (Gall et al., 1995) or on slide- stress- and glucocorticoid-induced negative feedback of these mounted sections (Vaidya et al., 1997). The two methods yielded equiv- brain regions. Conversely, increased RGS4 expression in the LC, alent results. In the free-floating hybridizations, rats were perfused by diminishing Gai function, is consistent with an upregulation of transcardially with 50 ml of saline followed by 400 ml of 4% paraformal- dehyde in 0.1 M sodium phosphate buffer, pH 7.4. Brains were post-fixed, the cAMP pathway known to occur in this brain region after m chronic stress. cryoprotected, and then sectioned at 30 m in the coronal plane with a microtome. Serial sections between 20.68 and 21.04 mm bregma, which includes the large majority of the locus coeruleus (Paxinos and Watson, MATERIALS AND METHODS 1982), were analyzed for this nucleus. In the slide hybridizations, brains were fresh frozen and then sectioned at 14 mm in the coronal plane with Animal treatments. Adult male Sprague Dawley rats (initial weight, 190– a cryostat. The pituitary was analyzed with the slide hybridization 240 gm; Charles River Laboratories, Wilmington, MA) were used in this method. Transverse pituitary sections (14 mm) were mounted on Ultra- study. Rats were caged in groups of two with food and water available ad Stick slides (Becton Dickinson, Rutherford, NJ). RNA-labeling densities libitum in a 12 hr light/dark cycle (lights off at 7 P.M.). All rats were were determined by densitizing autoradiographic film using Image anal- received from the vendor several days before initiating various treat- ysis software (NIH Image) as described previously (Gold et al., 1997). ments to habituate them to our vivarium. In the acute corticosterone For high resolution analysis, sections were dipped in autoradiographic treatment, rats received a single injection of either corticosterone (40 emulsion (NTB2; Eastman Kodak, Rochester, NY), exposed for 8 weeks, mg/kg in sesame oil, s.c.; Sigma, St. Louis, MO) or vehicle and were used developed with D19 (Eastman Kodak), fixed with Kodak fixer, counter- 6 hr later, at which time elevated plasma corticosterone levels have been stained with cresyl violet, and coverslipped with DPX (Aldrich, Milwau- documented (Pavlides et al., 1993). In the chronic corticosterone treat- kee, WI). ment, rats were implanted with sustained-release pellets (100 mg; 7 d release; Innovative Research of America, Toledo, OH) and used 7 d later as described (Ortiz et al., 1995). The control group received sham RESULTS surgery. Chronic unpredictable stress, which involves animals being ex- posed to two of eight different stressors per day for 10 d, was adminis- Regulation of RGS4 mRNA by chronic tered exactly according to published procedures (Ortiz et al., 1996).
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