Battle of the kinases: Integration of adrenal responses to cAMP, DG and Ca2+at the level of steroidogenic cytochromes P450 and 3ßHSD expression in H295R cells.
Abstract
While ACTH receptors (activating the protein kinase A pathway) are expressed throughout the human/bovine/ovine zona glomerulosa (zg) and zona fasciculata (zf), there are clear zonal differences in AII Type-1 receptor levels (activating protein kinase C/Ca2+), as well as resting membrane potential. Thus zg is most responsive to AII and K+ (Ca2+ signalling), while zf is less responsive to AII with no K+ response. Zonal function in turn requires differential expression of CYP17/3betaHSD and CYP11B2/CYP11B1. We have used the H295R cell to study how differential activation of kinase A, kinase C and Ca2+/calmodulin (CaM) kinases may alter the relative expression of the steroidogenic P450s and 3betaHSDII. While CYP11A, CYP17, 3betaHSDII, CYP21, and CYP11B1 are all induced by increases in cAMP, studies with TPA alone or in combination with forskolin reveal subsets of steroidogenic enzymes regulated either positively (CYP21, 3betaHSDII) or negatively (CYP17, CYP11A) by protein kinase C. Thus adrenal 3betaHSDII and CYP21 expression is high in zg and zf, but CYP17 is not expressed in the zg where AII activation of kinase C is highest. In turn both K+ and AII-induced elevation of Ca2+ strongly induces CYP11B2 but not CYP11B1, consistent with preferential expression of CYP11B2 in the zg. We conclude that differential signaling through kinase C and CaM kinases in addition to kinase A underlies zonal differences in both the early and late pathways involved in steroid hormone production within the adrenocortical zones.
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Aldosterone secretion is regulated mainly by angiotensin II, which activates the Gq protein coupled angiotensin 2 receptor and acts primarily through the protein kinase C pathway but also through Ca2+ signaling.
“In contrast, aldosterone secretion is regulated mainly by angiotensin II, which activates the Gqprotein coupled angiotensin 2 receptor (AT2R) , which acts primarily through the protein kinase C pathway but also through Ca 2+ signaling (166).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [166]
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The NCI-H295 cell line: a pluripotent model for human adrenocortical studies
Rainey, W. E., Bird, I. M., & Mason, J. I. (1994) · Molecular and Cellular Endocrinology · doi:10.1016/0303-7207(94)90277-1 · Cited by 297 · see citing works
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Self-citationCa(2+)-regulated expression of steroid hydroxylases in H295R human adrenocortical cells
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Self-citationAdrenal Androgen Biosynthesis with Special Attention to P450c17a
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Self-citationImmunohistochemical analysis of AT1receptor versus P450c17 and 3βHSD expression in ovine adrenals.
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Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management
Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556 · see citing works
Control of aldosterone secretion: a model for convergence in cellular signaling pathways
SPÄT, A., & HUNYADY, L. (2004) · Physiological Reviews · doi:10.1152/physrev.00030.2003 · Cited by 494 · see citing works
Wenzel, J., Grabinski, N., Knopp, C. A., Dendorfer, A., Ramanjaneya, M., Randeva, H. S., Ehrhart-Bornstein, M., Dominiak, P., & Jöhren, O. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.91034.2008 · Cited by 49 · see citing works
In the zone: understanding zona reticularis function and its transformation by adrenarche
Bird, I. M. (2012) · Journal of Endocrinology · doi:10.1530/joe-12-0246 · Cited by 23 · see citing works
Self-citation
- Authors
- Bird, I. M., Mason, J. I., & Rainey, W. E.
- Affiliations
- University of Wisconsin–Madison (US)
- Edinburgh Royal Infirmary (GB)
- The University of Texas Southwestern Medical Center (US)
- Venue
- Endocrine Research
- Publisher
- Informa UK Limited
- Published
- 1998-01
- Volume
- 24
- Issue
- 3-4
- Pages
- 345-354
- ISSN
- 0743-5800 (ISSN-L)
- 1532-4206
- OpenAlex
- W2006372853
- Cited by
- 27
- References
- 12
- Citations by year
- 2021: 1 · 2012: 1
- FWCI
- 0.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrine Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 56702)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK33104)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- steroidogenesis, cAMP signaling, protein kinase C, ACTH receptor, zona glomerulosa, zona fasciculata, CYP17, CYP11B2, CYP11B1, CYP21, CYP11A, H295R cells, tissue plasminogen activator, forskolin, potassium signaling
- MeSH terms
- Cyclic AMP, Adrenal Cortex, Adrenal Cortex Hormones, Calcium, Cell Line, Cytochrome P-450 Enzyme System, Deoxyglucose, Enzyme Activation, Humans, Phosphotransferases, 3-Hydroxysteroid Dehydrogenases
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