Testosterone Receptor

Cross references:  Steroids      Intracellular Receptors 
Receptors Evolution Timeline      Rodent Hormone-Nerve Interaction 
Testosterone Transcription Factor  Testosterone Serotonin Interaction 

Androgen receptor (Wiki) 
"The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor[6] which is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone [7] in the cytoplasm and then translocating into the nucleus."

File:Human androgen receptor and androgen binding.svg

Normal function of the androgen receptor.

    "
Testosterone (T) enters the cell and, if 5-alpha-reductase is present, is converted into dihydrotestone (DHT). Upon steroid binding, the androgen receptor (AR) undergoes a conformational change and releases heat shock proteins (hsps). Phosphorylation (P) occurs before or after steroid binding. The AR translocates to the nucleus where dimerization, DNA binding, and the recruitment of coactivators occur. Target genes are transcribed (mRNA) and translated into proteins.[2][3][4][5]
"   
    "
The main function of the androgen receptor is as a DNA binding transcription factor which regulates gene expression;[10] however, the androgen receptor has other functions as well.[11] Androgen regulated genes are critical for the development and maintenance of the male sexual phenotype.
"  "Up-regulation or activation of transcription results in increased synthesis of messenger RNA which in turn is transcribed by ribosomes to produce specific proteins.
    "
As has been also found for other steroid hormone receptors such as estrogen receptors, androgen receptors can have actions that are independent of their interactions with DNA.[11][19] Androgen receptors interact with certain signal transduction proteins in the cytoplasm.
Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of changes in gene transcription, such as changes in ion transport.
    "
In humans, the androgen receptor is encoded by the AR gene located on the X chromosome at Xq11-12.[20][21]


My comments
1.  Since "
Androgen ... can cause ... changes in ion transport " , this might explain the reported effect that testosterone has on the ionotropic 5-HT3R.  Unfortunately, references  [11]  and [19]  don't say anything about ion tronsport.  See below.     
2.  I'm surprised that the gene encoding the androgen receptor is on the X chromosome, rather than the Y chromosome.   


Reference  [11]  :  The Roles of Androgen Receptors and Androgen-Binding Proteins in Nongenomic Androgen Actions (Wiki) 
Full length HTML and PDF available online for free. 
Note:  This reference contains a large number of active links which can be accessed for a fuller understanding of the subject.  I read eleven of them.  Two of them, #6 and #8, were not useful, and I've deleted them.  The other nine are excerpted, below.   
 

#1 Rapid actions of androgens (PubMed) 
Only abstract available online.  Full article doesn't load at library.    
    "
The biological activity of androgens is thought to occur predominantly through binding to intracellular androgen-receptors, a member of the nuclear receptor family, that interact with specific nucleotide sequences to alter gene expression. This genomic-androgen effect typically takes at least more than half an hour. In contrast, the rapid or non-genomic actions of androgens are manifested within in seconds to few minutes. This rapid effect of androgens are manifold, ranging from activation of G-protein coupled membrane androgen-receptors or sex hormone-binding globulin receptors, stimulation of different protein kinases, to direct modulation of voltage- and ligand gated ion-channels and transporters. The physiological relevance of these non-genomic androgen actions has not yet been determined in detail. However, it may contribute to modulate several second messenger systems or transcription factors, which suggests a cross-talk between the fast non-genomic and the slow genomic pathway of androgens.


#2 Non-genomic Actions of Androgens (PubMed) 
Full length HTML and PDF available online for free. 
    "
Androgens have a specific binding site on neurotransmitter receptors, in particular the gamma-aminobutyric acid A (GABAA) receptor. Binding to GABAA receptors alters neuronal activity through changes in postsynaptic inhibition [91; 92]. In particular, DHT’s metabolite, 5α-androstane-3α, 17β-diol(3α-Diol), has been shown to alter recombinant rat GABAA receptor function in oocytes and it’s effect on sexual receptivity has been postulated to be via promotion of GABA stimulated chloride flux (Figure 2) [93; 94; 95].
    Hormone treatments also result in rapid negative and positive actions on other ion channel plasma membrane receptors, including N-methyl-D-aspartate (NMDA) receptors, glycine and nicotinic receptors as well as G protein-coupled receptors [96; 97; 98; 99; 100; 101].
    It is also well established that neuronal excitability mediated by ion channels is modulated by the local neuroactive steroids [102]. Thus, the rapid induction by neuroactive steroids at the plasma membrane could play an important role in the regulation of the brain function.

My comment:
For an interesting discussion of toadfish,
please see 
Teleost Dominance Hierarchies  . 
 
#3 Mechanisms and clinical relevance of androgens and
androgen receptor actions.
(PubMed) 
Full length PDF available online for free. 
I didn't find the text of this paper particularly helpful.  However, I like diagrams. 


If you want to know what the various abbreviations mean, click on the link and access the paper.  Otherwise, you may gradually become familiar with them by reading excerpts of other papers. 

#4 Androgens Transduce the Galphas-Mediated Activation of Protein Kinase A in Prostate Cells (PubMed) 
Full length HTML and PDF available online for free. 
    "
Androgen action is primarily mediated through the nuclear androgen receptor (AR) which acts as a ligand-dependent transcription factor. This mode of androgen action takes hours to manifest and is called the genomic pathway. The androgen-mediated genomic responses require activity of cyclic AMP (cAMP)-dependent protein kinase (PKA).
    Androgens also act through nongenomic pathways in certain cell types to evoke rapid responses (manifested in minutes) that are mediated through changes in ion currents and second messengers. Here, we show that androgen causes the rapid and cAMP-dependent activation of PKA in prostate cells.


#5 Rapid actions of steroid receptors in cellular sig
naling pathways.
(PubMed) 
Only abstract available online.  I got the PDF through the library.   
    "
The rapid effects of steroid hormones are manifold, ranging from activation of mitogen-activated protein kinases (MAPKs), adenylyl cyclase (AC), protein kinase C (PKC), and heterotrimeric guanosine triphosphate-binding proteins (G proteins).


From "Cited by...: 

Sex and estrogenic effects on coexpression of mRNAs in single ventromedial hypothalamic neurons.
(PubMed) 
Full length HTML and PDF available online for free.   
    "... estrogen-regulated gene expression ... What genes are coexpressed in neurons that have high levels of mRNAs for estrogen receptors (ERs)? ... An extremely high proportion of neurons expressing ... ER also coexpress mRNA for the oxytocin receptor (OTR)
My comment
I still don't understand.  When they write about mRNAs for ER or OTR, do the mRNAs code for more ER or OTR or do the mRNAs code for the proteins that are the result of activation of ER or OTR?  And if so, for what protein are they coding?   

#7 Non-genomic actions of sex steroid hormones (PubMed) 
Full length PDF available online for free. 
    "Ubiquitous regulatory cascades such as mitogen-activated protein kinases, the phosphatidylinositol 3-OH kinase and tyrosine kinases are modulated through non-transcriptional mechanisms by steroid hormones. Furthermore, steroid hormone receptor modulation of cell membrane-associated molecules such as ion channels and Gprotein-coupled receptors has been shown.
    Tissues traditionally considered as ‘non-targets’ for classical steroid actions are instead found to be vividly regulated by non-genomic mechanisms. ... The evidence collected in the past years indicates that
target cells and organs are regulated by a complex interplay of genomic and non-genomic signaling mechanisms of steroid hormones ..." 

#9 Control of CNS Neuronal Excitability by Estrogens via Membrane Initiated Signaling (PubMed) 
Full length HTML and PDF available online for free.  
    "
It has been known for a number of years that 17β-estradiol (E2) has acute, membrane-initiated signaling actions in the brain ...One view is that both the nuclear and plasma membrane-associated ERs are products of the same genes ...

My comment
So,
when they write about "mRNAs for ER", as in the paper, above, perhaps they really do mean mRNA to produce more of the receptor rather than mRNA to produce some other protein as a consequence of activation of the receptor.     

#10 Estrogen receptor beta regulates the expression of tryptophan-hydroxylase 2 mRNA within serotonergic neurons of the rat dorsal raphe nuclei (PubMed) 
Full length HTML and PDF available online for free. 
    "
All 5-HT neurons express tryptophan hydroxylase-2 (TPH2) ... Tryptophan-hydroxylase 2 (TPH2), the brain-specific version of TPH (Walther et al., 2003; Zhang et al., 2004), catalyses the rate-limiting step of 5-HT synthesis. Disruption or dysfunction of the tph2 gene is strongly correlated with affective disorders (Zill et al., 2004; Zhang et al., 2005; Haghighi et al., 2008), and abnormal tph2 mRNA expression may be responsible for many of those pathologies.
"   
    "
In conclusion, our results show that chronic, local activation of ERbeta alters tph2 mRNA expression in the dorsal raphe nucleus (DRN) in a subregion-dependent manner, and, at the same time, facilitates active stress-coping behavior.
"
My comment
This 2009 paper is the first time I've seen a clear distinction between the receptor, the gene, the mRNA coded by the gene, and the gene product.  In this instance, the receptor is ERbeta, the gene is 
tph2, the consequence of receptor activation is tph2 mRNA and the protein coded by the mRNA is tryptophan-hydroxylase 2.    HOORAY!!    
Note that the name of the gene, tph2 is in italics. 

#11 Estrogen decreases 5-HT1B autoreceptor mRNA in selective subregion of rat dorsal raphe nucleus: inverse association between gene expression and anxiety behavior in the open field (PubMed) 
Full length HTML and PDF available online for free. 
    "
Animal studies show that estrogen alters the DRN 5-HT system at multiple control points, including synthesis, release and reuptake (Rubinow et al., 1998). For instance, estrogen has been shown to increase the basal firing rate of serotonergic neurons in female rats (Robichaud and Debonnel, 2005), to increase 5-HT2A and 5-HT transporter mRNA in the DRN and binding sites in various forebrain regions of ovariectomized (OVX)
rats (McQueen et al., 1997, Sumner et al., 1999).
    In addition, we have recently shown that chronic estrogen treatment in OVX rats increases tryptophan hydroxylase-2 (TPH2) mRNA in selective subregions of the dorsal and median raphe (Hiroi et al., 2006), suggesting that estrogen increases the capacity for serotonin biosynthesis. 
   Autoreceptors are another important means of regulating serotonergic function. For example, somatodendritic 5-HT1A autoreceptors in DRN decrease neuronal firing (Sharp and Hjorth, 1990), thereby limiting 5-HT release from axons and dendrites.
    On the other hand, 5-HT1B autoreceptors are localized in terminals of the DRN axon projections throughout the forebrain where they regulate synthesis, release, and reuptake of 5-HT in a region-specific
manner (Hoyer and Middlemiss, 1989, Hjorth et al., 1995, Barnes and Sharp, 1999, Daws et al., 2000). Thus, 5-HT1A autoreceptors alter DRN neuron firing rates at the cell body, whereas 5-HT1B autoreceptors provide regional refinement of synaptic 5-HT.
    Estrogen has been shown to have no effect on the 5-HT1A mRNA levels in rat DRN (Birzniece et al., 2001).

    "
Estrogen selectively decreased 5-HT1B mRNA in the mVM DRN and this decrease was associated with increased TPH2 mRNA, suggesting that estrogen increases the availability of 5-HT in specific regions of the forebrain via a combined effect of disinhibition of 5-HT release from and increased biosynthesis of 5-HT in selective terminal regions of the forebrain.




Reference 
[19] :  Testosterone activates mitogen-activated protein kinase and the cAMP response element binding protein transcription factor in Sertoli cells (Wiki) 
Full length HTML and PDF available online for free. 
    "
In the classical view of androgen action, binding of androgen to its receptor produces a conformational change in AR such that the receptor–steroid complex has high affinity for specific DNA regulatory elements and is able to stimulate gene transcription (5).

    "Numerous genes and proteins are up-regulated in response to testosterone (810)"

My comment
I feel like I'm grasping at straws, but I'll go ahead and check out this reference.  
These may be what I'm looking for.  I'll look at references 5 and  810 , below. 

5. 
Analysis of the mechanism of steroid hormone receptor-dependent gene activation in cell-free systems.
  (PubMed) 
Only abstract available online.  Paywalled text.

    From "Related citations" 


Coactivation and corepression in transcriptional regulation by steroid/nuclear hormone receptors
  (PubMed) 
Only abstract available online.    See  Steroids 


8. Roberts, K. & Griswold, M. D. (1989) Endocrinology 125, 1174–1179.
Testosterone induction of cellular proteins in cultured Sertoli cells from hypophysectomized rats and rats of different ages.
[PubMed
Only abstract available online. 
    "
Two abundant proteins ... were consistently increased in response to testosterone treatment in ... cultured Sertoli cells. Two other proteins ... were decreased with testosterone ... . Densitometric scanning of the gels revealed changes in several proteins of low abundance (i.e. proteins that represent less than 0.2% of the total incorporated radioactivity on the gel) in response to testosterone.

My comment
This 1989 paper wasn't able to specify that the increase or decrease in 4+ proteins was a consequence in the binding of
testosterone transcription factor to 4+ different segments of DNA.  However, it did offer the possibility. 


9. Cheng, C. Y., Mather, J. P., Byer, A. L. & Bardin, C. W. (1986) Endocrinology 118, 480–488.
Identification of hormonally responsive proteins in primary Sertoli cell culture medium by anion-exchange high performance liquid chromatography.

 [PubMed
Only abstract available online.  Too old to be of much help. 


10. Kokontis, J. & Liao, S. (1999) Vitam. Horm. (San Francisco) 55, 219–307.
No abstract available. 
Searching PubMed for 'Kokontis J. Liao S' yielded 30 hits, but they weren't any help. 


Androgen Receptor Interactions
This link provides a list of 60 cellular components with which the androgen receptor interacts.  I didn't recognize any serotonin receptors among them. 
These are the links of potential interest: 
   
I read the first 24 links, through
and didn't find anything useful. 


Ontogeny and Autoregulation of Androgen Receptor mRNA Expression in the Nervous System (Goog) 
Full length HTML available online for free. 
The "Find" function did not locate either "serotonin" or "5-HT". 


Anabolic-androgenic steroid treatment induces beha... (Goog) 
    Search Terms: "androgen receptor mrna serotonin" 
    Come back to this.   
Only abstract available online for free.   
    Probably available through library. 
Anabolic-androgenic steroid treatment induces behavioral disinhibition and downregulation of serotonin receptor messenger RNA in the prefrontal cortex and amygdala of male mice



Come back to: (Google Search) "testosterone transcription factor"




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