Non Genomic Effects Of Steroid Hormones Biology Essay

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Steroid hormones are lipid soluble molecules which are all derived from cholesterol via a number of enzyme reactions in the gonads and adrenal glands. Steroid hormones can be classified into 5 groups depending on the receptors they bind to. Glucocorticoids, mineralocorticoids, androgens, estrogens, and progestagens. [1,2]

Over the pass 2 decades there has been a traditional hypothesis that is accepted by all scientist of how steroid hormones carry out their actions. This hypothesis is commonly referred to as the genomic actions of steroid hormones.

Steroid hormones are made "on demand" and released once synthesised. They are not stored like protein hormones. Once steroid hormones are released into the circulation they must travel to their target tissue where they carry out their action, however steroid hormones do not favour the aqueous media of the blood, thus why they bind to serum proteins present within the blood medium. For example Estrogens and androgens are transported in circulation by being bound to sex hormone binding protein (SHBG). Glucocorticoids and progesterone are transported in circulation by being bound to corticosteroid-binding globulin (CBG). These binding protein transport steroid hormones and release them locally to the target tissue. Only free hormones are active, thus once released from there binding protein, the steroid hormone, as they are lipid soluble can freely diffuse into the target cell. Once inside the target cell, these steroid hormones explicit their response by binding to specific receptors which are ligand-inducible transcription factors. These receptors are largely localized within the nucleus. Once the steroid hormone has bound to the receptor, the newly formed steroid-receptor complex detaches from cytoplasmic chaperone proteins such as heat shock proteins, thus resulting in formation of a receptor dimer. The receptor dimer binds to DNA and regulates the rate of transcription of specific genes and as a result the physiological effects.[2]

These genomic action that occur within the nucleus often take time, several hours to days, however recent studies have shown that certain steroid hormone can act within seconds, for example when 17-β-estradiol (E2)was administered intravenously to a ovariectmized rat, resulted in uterine cAMP levels to double within 15 seconds of administration. Given such rapid response the likelihood that gene transcription has occurred is very unlikely, thus suggesting that there is a strong possibility that steroid hormones may have non- genomic actions, by which they do not influence the transcription of genes.[3]

Additional evidence for this argument is provided in an In vitro study which analysed the effects of steroid hormone aldosterone on sodium ion exchange in dog erythrocytes. Erythrocytes are devoid of nucleus; therefore these cells do not contain DNA for transcription to occur, and therefore no genomic actions. As a results this study emphasises that steroid must act via a alternative pathways which does not require transcription of genes, however the mechanism behind how aldosterone is involved in sodium ion exchange is still yet to be discovered, but can be safely said that aldosterone acts in a non-genomic fashion. [4]

Over the years there have been more studies carried out that support the evidence provided so far, One of such studies included the discovery of events in which steroid hormones are still able produce the physiological response even in the presence of transcriptional and protein synthesis inhibitors, this again indicated that the steroid hormone function via a non-genomic manner. [5] Supplementary evidence was provide for non genomic actions of steroid hormones, when another tool was used to prevent the entry of steroid hormone into the target cell, by binding the steroid hormone to bovine serum albumin, as physiological effects are still seen, it is assumed that it is very likely the steroid hormone acts via receptors present on the surface of the cell, thus non- genomically. However this evidence has had some controversial views as endocytosis of the steroid hormone into the target cell has not yet been ruled out. [6]

The most prominent evidence of non- genomic actions of steroid hormones was the discovery of steroid receptors embedded in the plasma membrane that may be possibly responsible for the non genomic actions of steroid hormones and provide an explanation of such rapid responses of certain steroid hormones. This astounding evidence was first brought to light by Pietras and Szego in 1970 whom identified the presence of membrane bound receptors of estridiol in the endometrial cells of the uterus. [5] The membrane bound receptors are thought to use various different signalling mechanisms that are not associated with transcription of genes, thus are considered to play a role in non- genomic action.

Since this study in 1970 , further studies have been carried out on membrane bound estrogens receptors , these studies show that these receptors have been involved in rapid reactions such as regulating ion channels in cardiac muscle, [7] activating adenylate cyclase production and phospholipase C activity, [5] furthermore they have been found to be bound to integral proteins and form complexes with tyrosine kinase and G proteins. an example of such receptor complexes that have been identified is the G protein coupling rector GPR30 which is found embed in the plasma membrane and the endoplasmic reticulum, has the ability to bind estrogen , and explicit a non genomic response by stimulating the activation of protein kinase such as , Erk-1 and Erk-2, [8] and calcium signalling. [2]

There have been controversies between scientists into the structure and identity of distinct isoforms of estrogen receptors (ER) that contain transmembrane sequences. in early studies immunological identification methods were used to identify the structures of these membrane localised receptors it was suggested from this study that there may be homology sequences between classical estrogen receptors and that of the membrane bound estrogen receptors , however due to insufficient amount of evidence this theory was dismissed. Nevertheless since then there is now a natural growing agreement between scientist that classical ER have the ability to localise in the membrane , and therefore these membrane bound ER are indeed structurally similar to the classical ER. There have been various evidence provided for this argument, such as when membrane bound ER were isolated from breast cancer and analysed they showed to have the same mass spectrum as classical ER. In agreements with this are recent transfection studies which propose the existence of a saturable transport mechanism for the membrane-bound ER pool[3], therefore both ERα and ERβ can localize to membrane and be used to form membrane ER. [3,5] However another study in which the genes for the classical estrogen receptors are knocked out in a mouse, it was noticed that this mouse still showed estridiol-induced extracellular regulated kinase phosphorylation. This indicated that there is a presence on another estrogen receptor that does not show the structural characteristics of classical estrogen receptors. [9]

Since the studies in 1970 there have now been many membrane bound steroid receptors have been identified such as, testosterone membrane binding sites have been identified on rat osteoblasts, macrophages and T lymphocytes [5]. Additionally there has been a membrane bound steroid receptor that has been identified for minleralocorticoids on kidney cell membranes. Mineralocorticoid receptors were identified by the use of aldoestrone analogue containing iodine. This analogue was then used to detect and identify the specific binding sites. This analogue had a highly specific activity which was able to plasma membrane sites that have a subnanomolar affinity range., further tests were carried to determine the specificity of these receptor. Cortisol a glucocorticoid, remained inactive until it was in micromolar concentration and fludeocortsone which has a high mineralocorticoid potency showed to have medium responses. The conclusion of such findings indicates that this membrane bound steroid receptor is highly specific for mineralocorticoid. [6]

There has been an investigation into the structure of such non-classical mineralocorticoid receptor. In a particular investigation, the gene coding for the classical mineralocorticoid receptor was knocked out in a mouse. The mouse was then stimulated by aldosterone and intracellular [Ca2+] levels were measured from its skin fibroblasts, the values obtained was compared to values obtained from a wild type mouse's skin fibroblasts which still contained the genes for classical mineralocorticoid receptors. The results obtained show that there were no considerable change in intracellular calcium concentration of the wild type and knockout mouse. This suggest that there is a presence of mineralocorticoid receptors that do not have the same structure as classical mineralocorticoid receptors , however this study does not provide prove that these receptors reside within the membrane. [9]

There have also been reports of various glucocorticoid effects that have been suggested to function via a membrane bound receptor. Theses membrane bound receptors have been identified in plasma membranes in chicken, mouse and rat liver. A specific membrane receptor which has high affinity binding site with low binding capacity for Cortisol was analysed via SDS-PAGE, which revelled the receptor to consist of two subunit, molecular weight of 52 and 57kDa respectively. The weights of the subunit and the binding affinity of the membrane receptors are just some of the characteristic that differ from that of classical glucocorticoid receptors (GR) , this suggests that the membrane GR is structurally different form that of classical GR. However other studies have shown evidence of forms of membrane bound receptors GR that are homologous to classical GR indicating that they are structurally similar and carry out non-genomic actions. [9]

To conclude, most scientists have now accepted that there are indeed non-genomic actions by steroid hormones. However, there are still debates about the mechanism of such actions, and in trying to determine the receptors which are involved in non-genomic actions. There is many evidence which supports the existence of membrane bound steroid receptors. However the controversy lies in determining the structures of such membrane bound steroid receptors and if they are structural similar to classical steroid receptors or they can be classed as non classical. Evidence stated above suggests both the existence of classical receptors involved in non-genomic actions as well as structurally distinct receptors, thus the evidence so far is not conclusive. However the studies do provide a basis for further studies to be carried out on.