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Cellular Localization of Receptors Mediating the Actions of Steroid Hormones

Barbara M. Judy, Wade V. Welshons

10.1002/cphy.cp070117

Source: Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology

Originally published: 1998

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Nuclear Localization of Most Unliganded Steroid Receptors
1.1 Basis for the Initial Two‐Step Translocation Model of Steroid Action and Location
1.2 Current Nuclear Localization Model for Most Steroid Receptors
1.3 Glucocorticoid Receptor Localization
2 Nuclear Import and Export of Steroid Receptors
2.1 Entry of Proteins Into the Nucleus
2.2 Nuclear Localization Signals
2.3 Mechanism of Nuclear Import
2.4 Nuclear Export and Nucleocytoplasmic Shuttling
2.5 Conclusions
3 Alternate Steroid Receptors and Nongenomic Steroid Responses
3.1 Estrogen Receptor‐β
3.2 Glucocorticoids
3.3 Mineralocorticoids
3.4 Progesterone
3.5 Estrogen
3.6 1,25‐Dihydroxyvitamin D3
3.7 Testosterone
4 Conclusions
Figure 1. Figure 1.

Nuclear receptor model (A) and translocation model (B) for steroid hormonal action. RNAP, RNA polymerase; TFs, transcription factors; SRE, steroid response element.
Figure 2. Figure 2.

Schematic map of the structural and functional organization of steroid receptors. Conserved regions C and E are indicated as boxes and a black bar illustrates regions A/B, D, and F. Domain functions are listed above and below NLS, nuclear localization signal; TAF, transcription activation function.
Figure 3. Figure 3.

Steps of the nuclear protein‐import cycle. Nuclear localization signal (NLS)‐containing proteins bind to the importin heterodimer (NLS receptor) in the cytosol. The NLS interacts primarily with the α‐subunit; the importin‐β‐binding domain of α mediates heterodimerization. Binding of NLS to α can precede α‐β interaction. The β‐subunit mediates docking of the complex at the nuclear pore complex. Translocation involves GTP hydrolysis by Ran and is probably a multistep process. The α‐β heterodimer dissociates, and α enters the nucleoplasm with the substrate. Dissociation of α from the nuclear protein must then occur. For a further round of import, the subunits of importin are returned to the cytoplasm, possibly separately.

[Reprinted with permission from D. Görlich and I. W. Mattaj 53. Science 271: 1513–1518. Copyright 1996, American Association for the Advancement of Science.]
Figure 4. Figure 4.

Inhibition of male sexual behavior. A: Latency of response to corticosterone. Males were injected with 32 nmol (11 μg) of corticosterone (filled circles) or vehicle (open squares), n = 14. Arrow indicates time of addition of females to tanks. Data are reported as cumulative percentage of claspers at 1 min intervals.* Males injected with corticosterone were inhibited significantly within 3 min of testing (Fisher's exact test, P = 0.025). B: Linear relationship between potency of steroids in inhibition of [3H]corticosterone binding (ordinate) and potency in inhibition of sexual behavior (abscissa). Males were injected with one of five to seven doses of steroid or vehicle (n = 24 for each dose of steroid, except n = 14 for RU 28362). Data were recorded as number of claspers in 20 min tests (except cortisol, for which 60 min tests were performed late in the breeding season).

[Reprinted with permission from M. Orchinik, T. F. Murray, and F. L. Moore 131. Science 252: 1848–1851. Copyright 1991, American Association for the Advancement of Science.]
Figure 5. Figure 5.

Dose response of progesterone; 5β‐pregnan‐3β‐ol‐20‐one (epipregnanolone); 5α‐pregnane‐3α‐21‐diol‐20‐one (5α‐THDOC); 5α‐pregnan‐3α‐ol‐11,20‐dione (alfaxalone); 5α‐pregnan‐3α‐ol‐20‐one (allopregnanolone); and 5β‐pregnan‐3α‐ol‐20‐one (pregnanolone) to elevate [Ca2+]i in human sperm. Sperm were loaded with fura‐2, and increases in [Ca2+]i induced by each steroid were determined by measuring the difference between the basal level of [Ca2+]i (before steroid addition) and the maximum level of [Ca2+]i attained (usually observed approximately 20 s after steroid addition). Each value shown is the mean of triplicate determinations. Data are expressed as percentage of effect observed with 10 μM progesterone (a maximally effective concentration).

[From P. F. Blackmore 10. Mol. Cell. Endocrinol. 104: 237–243, 1994. Reproduced by copyright permission of Elsevier Science Ireland Ltd.]
Figure 6. Figure 6.

Prolactin release in immunoseparated cell populations. “+” cells are membrane estrogen receptor‐enriched; “−” cells are membrane estrogen receptor‐depleted. Data are from three independent experiments; error bars are the standard of the mean. ctrl, control (ethanol vehicle); 17β‐E2, 17β‐estradiol; *, significantly different from the equivalent time control.

[From T. C. Pappas et al. Endocrine 3: 743–749, 1995. Reproduced by copyright permission of the Humana Press.]
Figure 7. Figure 7.

Effect of progestins and androgens on chicken granulosa cell [Ca2+]i. Granulosa cells were treated with progesterone (PROG; 10−–10−5M; A), pregnenolone (PREG; 10−7–10−5 M; B), testosterone (T; 10−7–10−5 M; C), or androstenedione (ADIONE; 10−8–10−5 M; D) before stimulation with estradiol‐17β (E2, 10−7 M). Arrowheads indicate the time of addition of steroids.

[From P. Morley et al. 118 Endocrinology 131: 1305–1311, 1992. Reproduced by copyright permission of the Endocrine Society.]
Figure 8. Figure 8.

Effect of 1,25(OH)2D3, the phorbol ester 12‐O‐tetradecanoyl phorbol = 13‐acetate (TPA), and forskolin on the appearance of 45Ca2+ in the venous effluent of perfused duodena from normal chicks. Each duodenum, filled with 45CaCl2 (5 μCi/ml) in Grey's balanced saline solution (GBSS), was perfused vascularly (24° C) for the first 20 min with control medium (GBSS containing 0.125% bovine serum albumin and 0.5 μl/ml ethanol) and then with 130 pm 1,25 (OH)2D3 (open circles), 100 nm TPA (filled circles), 10 μM forskolin (open triangles), or control medium (open squares) for up to 30 min. Values are the mean ± SD of four duodena for each treatment.

[From A. R. de Boland and A. Norman 28. Endocrinology 127: 39–45, 1990. Reproduced by copyright permission of the Endocrine Society.]
Figure 9. Figure 9.

Effect of testosterone on 45Ca influx and efflux in ventricle cubes. Left panel: 45Ca influx. Cubes were preincubated in physiological salt solution at 37° C for 10 min. At zero time, 45Ca (≃ 1 μCi/ml) and 10−8 M testosterone (open circles) or vehicle (filled circles) were added, and incubations were terminated at given times. Right panel: 45Ca efflux. Cubes were preincubated with 45Ca (≃ 5 μCi/ml) in physiological salt solution for 20 min, washed, and incubated in fresh medium containing 10−8 M testosterone (open circles) or vehicle (filled circles). 45Ca efflux was determined at given times in supernatant samples and expressed as percentage of total 45Ca in ventricle cubes at the beginning of incubation. Data are mean ± SEM (n = 3). *P < 0.05; **P < 0.01 (vs. control).

[From Koenig et al 88. Circ. Res. 64: 417–426, 1989. Reproduced by copyright permission of the American Heart Association.]


Figure 1.

Nuclear receptor model (A) and translocation model (B) for steroid hormonal action. RNAP, RNA polymerase; TFs, transcription factors; SRE, steroid response element.



Figure 2.

Schematic map of the structural and functional organization of steroid receptors. Conserved regions C and E are indicated as boxes and a black bar illustrates regions A/B, D, and F. Domain functions are listed above and below NLS, nuclear localization signal; TAF, transcription activation function.



Figure 3.

Steps of the nuclear protein‐import cycle. Nuclear localization signal (NLS)‐containing proteins bind to the importin heterodimer (NLS receptor) in the cytosol. The NLS interacts primarily with the α‐subunit; the importin‐β‐binding domain of α mediates heterodimerization. Binding of NLS to α can precede α‐β interaction. The β‐subunit mediates docking of the complex at the nuclear pore complex. Translocation involves GTP hydrolysis by Ran and is probably a multistep process. The α‐β heterodimer dissociates, and α enters the nucleoplasm with the substrate. Dissociation of α from the nuclear protein must then occur. For a further round of import, the subunits of importin are returned to the cytoplasm, possibly separately.

[Reprinted with permission from D. Görlich and I. W. Mattaj 53. Science 271: 1513–1518. Copyright 1996, American Association for the Advancement of Science.]


Figure 4.

Inhibition of male sexual behavior. A: Latency of response to corticosterone. Males were injected with 32 nmol (11 μg) of corticosterone (filled circles) or vehicle (open squares), n = 14. Arrow indicates time of addition of females to tanks. Data are reported as cumulative percentage of claspers at 1 min intervals.* Males injected with corticosterone were inhibited significantly within 3 min of testing (Fisher's exact test, P = 0.025). B: Linear relationship between potency of steroids in inhibition of [3H]corticosterone binding (ordinate) and potency in inhibition of sexual behavior (abscissa). Males were injected with one of five to seven doses of steroid or vehicle (n = 24 for each dose of steroid, except n = 14 for RU 28362). Data were recorded as number of claspers in 20 min tests (except cortisol, for which 60 min tests were performed late in the breeding season).

[Reprinted with permission from M. Orchinik, T. F. Murray, and F. L. Moore 131. Science 252: 1848–1851. Copyright 1991, American Association for the Advancement of Science.]


Figure 5.

Dose response of progesterone; 5β‐pregnan‐3β‐ol‐20‐one (epipregnanolone); 5α‐pregnane‐3α‐21‐diol‐20‐one (5α‐THDOC); 5α‐pregnan‐3α‐ol‐11,20‐dione (alfaxalone); 5α‐pregnan‐3α‐ol‐20‐one (allopregnanolone); and 5β‐pregnan‐3α‐ol‐20‐one (pregnanolone) to elevate [Ca2+]i in human sperm. Sperm were loaded with fura‐2, and increases in [Ca2+]i induced by each steroid were determined by measuring the difference between the basal level of [Ca2+]i (before steroid addition) and the maximum level of [Ca2+]i attained (usually observed approximately 20 s after steroid addition). Each value shown is the mean of triplicate determinations. Data are expressed as percentage of effect observed with 10 μM progesterone (a maximally effective concentration).

[From P. F. Blackmore 10. Mol. Cell. Endocrinol. 104: 237–243, 1994. Reproduced by copyright permission of Elsevier Science Ireland Ltd.]


Figure 6.

Prolactin release in immunoseparated cell populations. “+” cells are membrane estrogen receptor‐enriched; “−” cells are membrane estrogen receptor‐depleted. Data are from three independent experiments; error bars are the standard of the mean. ctrl, control (ethanol vehicle); 17β‐E2, 17β‐estradiol; *, significantly different from the equivalent time control.

[From T. C. Pappas et al. Endocrine 3: 743–749, 1995. Reproduced by copyright permission of the Humana Press.]


Figure 7.

Effect of progestins and androgens on chicken granulosa cell [Ca2+]i. Granulosa cells were treated with progesterone (PROG; 10−–10−5M; A), pregnenolone (PREG; 10−7–10−5 M; B), testosterone (T; 10−7–10−5 M; C), or androstenedione (ADIONE; 10−8–10−5 M; D) before stimulation with estradiol‐17β (E2, 10−7 M). Arrowheads indicate the time of addition of steroids.

[From P. Morley et al. 118 Endocrinology 131: 1305–1311, 1992. Reproduced by copyright permission of the Endocrine Society.]


Figure 8.

Effect of 1,25(OH)2D3, the phorbol ester 12‐O‐tetradecanoyl phorbol = 13‐acetate (TPA), and forskolin on the appearance of 45Ca2+ in the venous effluent of perfused duodena from normal chicks. Each duodenum, filled with 45CaCl2 (5 μCi/ml) in Grey's balanced saline solution (GBSS), was perfused vascularly (24° C) for the first 20 min with control medium (GBSS containing 0.125% bovine serum albumin and 0.5 μl/ml ethanol) and then with 130 pm 1,25 (OH)2D3 (open circles), 100 nm TPA (filled circles), 10 μM forskolin (open triangles), or control medium (open squares) for up to 30 min. Values are the mean ± SD of four duodena for each treatment.

[From A. R. de Boland and A. Norman 28. Endocrinology 127: 39–45, 1990. Reproduced by copyright permission of the Endocrine Society.]


Figure 9.

Effect of testosterone on 45Ca influx and efflux in ventricle cubes. Left panel: 45Ca influx. Cubes were preincubated in physiological salt solution at 37° C for 10 min. At zero time, 45Ca (≃ 1 μCi/ml) and 10−8 M testosterone (open circles) or vehicle (filled circles) were added, and incubations were terminated at given times. Right panel: 45Ca efflux. Cubes were preincubated with 45Ca (≃ 5 μCi/ml) in physiological salt solution for 20 min, washed, and incubated in fresh medium containing 10−8 M testosterone (open circles) or vehicle (filled circles). 45Ca efflux was determined at given times in supernatant samples and expressed as percentage of total 45Ca in ventricle cubes at the beginning of incubation. Data are mean ± SEM (n = 3). *P < 0.05; **P < 0.01 (vs. control).

[From Koenig et al 88. Circ. Res. 64: 417–426, 1989. Reproduced by copyright permission of the American Heart Association.]
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Article Title: Cellular Localization of Receptors Mediating the Actions of Steroid Hormones
 

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Barbara M. Judy, Wade V. Welshons. Cellular Localization of Receptors Mediating the Actions of Steroid Hormones. Compr Physiol 2011, Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology: 437-460. First published in print 1998. doi: 10.1002/cphy.cp070117