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How Do Androgens (and Other Steroid Hormones) Work?
Testosterone was first isolated, then synthesized in 1935. For this accomplishment, the Nobel Prize in Chemistry was awarded in 1939. Numerous pharmaceutical analogs were synthesized during the following decades, yet the precise mechanisms of action of androgenic compounds remained mysterious, until recently. A significant milestone occurred in 1988, when the androgen receptor (AR) was successfully cloned. This improved understanding of the structure and function of the AR led directly to breakthroughs in several AR-related diseases, such as prostate and bladder cancer, and Kennedy's neuron disease (a rare motor disorder similar to Lou Gehrig's disease, that affects only men). More recent advances in our understanding of genetics and improved laboratory methodologies have resulted in an unprecedented explosion of knowledge concerning the modes and pathways of action of androgens and other hormones of the nuclear receptor superfamily. However, with this increased understanding comes a better appreciation for the many complexities involved, reminding us how little we really know. We all realize that androgens are intimately involved in making us who we are, and have a very profound effect upon our health and vitality; many take supplemental androgens. Yet, how well do you really understand the details involved in the specific pathways by which androgens function? Most will say that androgens bind to cellular receptors and cause the cell to produce protein. While this is by no means incorrect, far more is now known about androgen activity than what most will remember from their old biology textbook. In addition to the classical AR model of nuclear transcription, there are at least 3 other pathways by which androgens function. In addition to effects brought about by changes in genetic transcription, androgens are known to produce many immediate, non-genetic effects.
Three topics for more detailed future discussions:
The Structure and Function of the Androgen Receptor
This topic would cover the various binding domains, basically how the AR works in different tissues that express it, and why the effects vary so much in different cell lines, etc.
Androgenic Coregulators
This topic would cover the effects of various transcription factors, and other interacting proteins.
This topic could also cover the epigenetic regulation of function, including a discussion of the important role of chromatin remodelers, histone modifiers, chaperones, etc.
Non-transcriptional Effects
A discussion of the many important effects that do not result from genetic transcription/translation. These effects are distinguished by their speed. They take place within a matter of seconds to minutes, much too fast to be explained by the classical model of genetic transcription, followed by the translation of mRNA, and the eventual processing of proteins to produce measurable outcomes.
Four Pathways of Function:
The Classical AR Model
According to the classical model, free androgens, which are lipophilic, cross the cellular membrane by passive diffusion. Once inside the cell, they bind to the AR. The resulting complex is translocated to the nucleus. It is also dimerized, which means that two receptors become attached to each other. Within the nucleus, the dimerized receptors bind to “hormone response elements”, which are specific DNA sequences located in promoters of target genes, resulting in transcription of the target genes.
SHBG Pathway
Androgens can also work while bound to SHBG by activating the SHBG-receptor in the membrane, without entering the cytoplasm. This can incease PKA (protein kinase A) activity altering phosphorylation status of AR and AR coregulators, and in this way affect transcription. www.ncbi.nlm.nih.gov: Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane. - PubMed - NCBI
Alternatively, SHBG can transport androgens across the cell membrane thru an endocytotic process, enabling them to bind to the AR inside the cell. www.ncbi.nlm.nih.gov: Cellular uptake of steroid carrier proteins--mechanisms and implications. - PubMed - NCBI
MAPK Pathway
Mitogen-Activated Protein Kinase is another way androgens can alter phosphorylation, and hence transcription. Bound AR interacts with the SH3 domain of the tyrosine kinase c-Src to activate the MAPK pathway and influence AR-mediated transcription via phosphorylation of coactivator/receptor complexes. endo.endojournals.org: Testosterone Activates Mitogen-Activated Protein Kinase via Src Kinase and the Epidermal Growth Factor Receptor in Sertoli Cells | Endocrinology | Oxford Academic
Membrane-bound Androgen Receptor Pathway
Androgens have been found to bind to the plasma membrane in many cell types. This has led many to believe that novel androgen receptors exist in cell membranes. Such a membrane AR could also explain how androgens are able to rapidly modulate the activity of ion channels (i.e. calcium). Androgens are also known to have a specific binding site on neurotransmitter receptors, like the GABA-A receptor. Binding to GABA-A receptors can alter postsynaptic inhibition, affecting neuronal activity. Androgens have an effect upon GnRH neurons, even though they do not express the classical AR. Such a membrane-bound AR, although thought to exist, has not yet been purified or cloned.
www.ncbi.nlm.nih.gov: Activation of Membrane Androgen Receptors in Colon Cancer Inhibits the Prosurvival Signals Akt/Bad In Vitro and In Vivo and Blocks Migration via Vinculin/Actin Signaling
www.ncbi.nlm.nih.gov: Altered GABAA receptor-mediated synaptic transmission disrupts the firing of gonadotropin-releasing hormone neurons in male mice under conditions that mimic steroid abuse
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1985867
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629475
Testosterone was first isolated, then synthesized in 1935. For this accomplishment, the Nobel Prize in Chemistry was awarded in 1939. Numerous pharmaceutical analogs were synthesized during the following decades, yet the precise mechanisms of action of androgenic compounds remained mysterious, until recently. A significant milestone occurred in 1988, when the androgen receptor (AR) was successfully cloned. This improved understanding of the structure and function of the AR led directly to breakthroughs in several AR-related diseases, such as prostate and bladder cancer, and Kennedy's neuron disease (a rare motor disorder similar to Lou Gehrig's disease, that affects only men). More recent advances in our understanding of genetics and improved laboratory methodologies have resulted in an unprecedented explosion of knowledge concerning the modes and pathways of action of androgens and other hormones of the nuclear receptor superfamily. However, with this increased understanding comes a better appreciation for the many complexities involved, reminding us how little we really know. We all realize that androgens are intimately involved in making us who we are, and have a very profound effect upon our health and vitality; many take supplemental androgens. Yet, how well do you really understand the details involved in the specific pathways by which androgens function? Most will say that androgens bind to cellular receptors and cause the cell to produce protein. While this is by no means incorrect, far more is now known about androgen activity than what most will remember from their old biology textbook. In addition to the classical AR model of nuclear transcription, there are at least 3 other pathways by which androgens function. In addition to effects brought about by changes in genetic transcription, androgens are known to produce many immediate, non-genetic effects.
Three topics for more detailed future discussions:
The Structure and Function of the Androgen Receptor
This topic would cover the various binding domains, basically how the AR works in different tissues that express it, and why the effects vary so much in different cell lines, etc.
Androgenic Coregulators
This topic would cover the effects of various transcription factors, and other interacting proteins.
This topic could also cover the epigenetic regulation of function, including a discussion of the important role of chromatin remodelers, histone modifiers, chaperones, etc.
Non-transcriptional Effects
A discussion of the many important effects that do not result from genetic transcription/translation. These effects are distinguished by their speed. They take place within a matter of seconds to minutes, much too fast to be explained by the classical model of genetic transcription, followed by the translation of mRNA, and the eventual processing of proteins to produce measurable outcomes.
Four Pathways of Function:
The Classical AR Model
According to the classical model, free androgens, which are lipophilic, cross the cellular membrane by passive diffusion. Once inside the cell, they bind to the AR. The resulting complex is translocated to the nucleus. It is also dimerized, which means that two receptors become attached to each other. Within the nucleus, the dimerized receptors bind to “hormone response elements”, which are specific DNA sequences located in promoters of target genes, resulting in transcription of the target genes.
SHBG Pathway
Androgens can also work while bound to SHBG by activating the SHBG-receptor in the membrane, without entering the cytoplasm. This can incease PKA (protein kinase A) activity altering phosphorylation status of AR and AR coregulators, and in this way affect transcription. www.ncbi.nlm.nih.gov: Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane. - PubMed - NCBI
Alternatively, SHBG can transport androgens across the cell membrane thru an endocytotic process, enabling them to bind to the AR inside the cell. www.ncbi.nlm.nih.gov: Cellular uptake of steroid carrier proteins--mechanisms and implications. - PubMed - NCBI
MAPK Pathway
Mitogen-Activated Protein Kinase is another way androgens can alter phosphorylation, and hence transcription. Bound AR interacts with the SH3 domain of the tyrosine kinase c-Src to activate the MAPK pathway and influence AR-mediated transcription via phosphorylation of coactivator/receptor complexes. endo.endojournals.org: Testosterone Activates Mitogen-Activated Protein Kinase via Src Kinase and the Epidermal Growth Factor Receptor in Sertoli Cells | Endocrinology | Oxford Academic
Membrane-bound Androgen Receptor Pathway
Androgens have been found to bind to the plasma membrane in many cell types. This has led many to believe that novel androgen receptors exist in cell membranes. Such a membrane AR could also explain how androgens are able to rapidly modulate the activity of ion channels (i.e. calcium). Androgens are also known to have a specific binding site on neurotransmitter receptors, like the GABA-A receptor. Binding to GABA-A receptors can alter postsynaptic inhibition, affecting neuronal activity. Androgens have an effect upon GnRH neurons, even though they do not express the classical AR. Such a membrane-bound AR, although thought to exist, has not yet been purified or cloned.
www.ncbi.nlm.nih.gov: Activation of Membrane Androgen Receptors in Colon Cancer Inhibits the Prosurvival Signals Akt/Bad In Vitro and In Vivo and Blocks Migration via Vinculin/Actin Signaling
www.ncbi.nlm.nih.gov: Altered GABAA receptor-mediated synaptic transmission disrupts the firing of gonadotropin-releasing hormone neurons in male mice under conditions that mimic steroid abuse
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1985867
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629475