Steroid hormones are usually transported in the blood stream by carrier proteins. At their target cells they are released and can then either bind to surface receptors or diffuse through the plasma membrane due to their lipophilic nature. In the cell they are bound to receptors that enter the nucleus and influence gene expression. Some aspects of this model are not clear to me:
1.) How do carrier proteins in the bloodstream "know" when to release the hormones? How are target cells recognized? The ability of steroid hormones to directly pass the plasma membrane makes specificity somewhat difficult to achieve.
2.) So most steroids can pass through the plasma membrane because they are lipophilic. But then they have to travel through the hydrophilic cytoplasm to reach their destination. Are steroid hormones amphiphilic? Or are they immediately bound to a receptor protein once they pass the plasma membrane?
3.) If steroid hormones are capable to pass the plasma membrane they should also be able to pass the nuclear membrane without being bound to a receptor protein, yet this does not seem to be the case. The lipid composition of plasma and nuclear membrane is different, but can this explain the differential diffusion behaviour of steroid hormones?
4.) How are steroid hormones that have served their purpose removed from the cell? Are there deactivating enzymes? If yes, how are these regulated? Or can the steroid hormones, once released from their receptors, simply diffuse out of the cell? If this is the case, how is a "re-binding" of the hormone to another receptor protein prevented?
I would appreciate if somebody could help me with these questions and/or point me to literature that explains these processes in more detail.
The mechanistically specific answers to your questions are complex and better answered by others. However, generally speaking:
1. Carrier proteins do not need to know when to release steroid hormones because the binding affinity between steroid hormones and their serum carriers is not very high. The off rates are probably high. When you think about the hypothalamic-pituitary-gonadal or hypothalamic-pituitary-adrenal axis, this makes sense. Serum cortisol or serum estrogen is more or less equally present throughout circulation. Its target effects are dictated by the presence of the receptors rather than the mobility of the ligand (since the ligand is everywhere).
2. The distance between the plasma membrane and various organelles looks quite large in a textbook, but this is for ease of depiction. In reality, many cells contain leaflets of ER and Golgi that are in close proximity to the PM and nuclear envelope. Moreover, in target tissues, the expression level of cognate receptors is relatively high such that there is a high probability that the steroid will collide with one of its receptors upon entering the cell.
3. I do not know if steroids can penetrate the nuclear envelope. Even if they could, they would not be able to influence transcription without being bound to their respective nuclear hormone receptors. It would not surprise me if their solubility in PM and nuclear envelope were different. All lipids are not created equally, and steroid hormones are significantly more hydrophilic than their parent cholesterol.
4. In most instances, steroids are cleared from circulation by dehydrogenases, reductases present in mitochondria and ER of the target tissue or elsewhere. Since the on/off rates of steroids are high, yes, there is continual diffusion in and out of cells. And as the serum levels of various steroids drop, eventually the intracellular level in target cells also drops. This is not only relevant for steroid degradation, but also for synthesis. For example: in early pregnancy, maternal cortisol is rapidly oxidized/inactivated by fetoplacental 11-beta-hydroxysteroid dehydrogenase 2 (11-HSD2). However, toward term, 11-HSD-1 expression increases in the chorioamnion, which reactivates cortisol and promotes a placental H-P-A feed-forward surge that ultimately triggers parturition. See this publication for more information: Article Enhancement of Glucocorticoid-Induced 11β-Hydroxysteroid Deh...
The mechanistically specific answers to your questions are complex and better answered by others. However, generally speaking:
1. Carrier proteins do not need to know when to release steroid hormones because the binding affinity between steroid hormones and their serum carriers is not very high. The off rates are probably high. When you think about the hypothalamic-pituitary-gonadal or hypothalamic-pituitary-adrenal axis, this makes sense. Serum cortisol or serum estrogen is more or less equally present throughout circulation. Its target effects are dictated by the presence of the receptors rather than the mobility of the ligand (since the ligand is everywhere).
2. The distance between the plasma membrane and various organelles looks quite large in a textbook, but this is for ease of depiction. In reality, many cells contain leaflets of ER and Golgi that are in close proximity to the PM and nuclear envelope. Moreover, in target tissues, the expression level of cognate receptors is relatively high such that there is a high probability that the steroid will collide with one of its receptors upon entering the cell.
3. I do not know if steroids can penetrate the nuclear envelope. Even if they could, they would not be able to influence transcription without being bound to their respective nuclear hormone receptors. It would not surprise me if their solubility in PM and nuclear envelope were different. All lipids are not created equally, and steroid hormones are significantly more hydrophilic than their parent cholesterol.
4. In most instances, steroids are cleared from circulation by dehydrogenases, reductases present in mitochondria and ER of the target tissue or elsewhere. Since the on/off rates of steroids are high, yes, there is continual diffusion in and out of cells. And as the serum levels of various steroids drop, eventually the intracellular level in target cells also drops. This is not only relevant for steroid degradation, but also for synthesis. For example: in early pregnancy, maternal cortisol is rapidly oxidized/inactivated by fetoplacental 11-beta-hydroxysteroid dehydrogenase 2 (11-HSD2). However, toward term, 11-HSD-1 expression increases in the chorioamnion, which reactivates cortisol and promotes a placental H-P-A feed-forward surge that ultimately triggers parturition. See this publication for more information: Article Enhancement of Glucocorticoid-Induced 11β-Hydroxysteroid Deh...
Excellent contribution, Damien.
Thank you very much for taking the time to answer my questions in such detail.
Kind regards,
Christian
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