Steroid hormone receptors
Вставка
- Опубліковано 10 лип 2017
- Nuclear receptors
Main article: nuclear receptor
Steroid receptors of the nuclear receptor family are all transcription factors. Depending upon the type of receptor, they are either located in the cytosol and move to the cell nucleus upon activation, or remain in the nucleus waiting for the steroid hormone to enter and activate them. This uptake into the nucleus is facilitated by nuclear localization signal (NLS) found in the hinge region of the receptor. This region of the receptor is covered up by heat shock proteins (HSPs) which bind the receptor until the hormone is present. Upon binding by the hormone the receptor undergoes a conformational change releasing the HSP, and the receptor together with the bound hormone enter the nucleus to act upon transcription.
Nuclear receptors
Subfamily 3: Estrogen Receptor-like
Group A: Estrogen receptor (Sex hormones: Estrogen)
1: Estrogen receptor-α (ERα; NR3A1, ESR1)
2: Estrogen receptor-β (ERβ; NR3A2, ESR2)
Group C: 3-Ketosteroid receptors
1: Glucocorticoid receptor (GR; NR3C1) (Cortisol)
2: Mineralocorticoid receptor (MR; NR3C2) (Aldosterone)
3: Progesterone receptor (PR; NR3C3, PGR) (Sex hormones: Progesterone)
4: Androgen receptor (AR; NR3C4, AR) (Sex hormones: Testosterone)
Structure
Intracellular steroid hormone receptors share a common structure of four units that are functionally homologous, so-called "domains":
Variable domain: It begins at the N-terminal and is the most variable domain between the different receptors.
DNA binding domain: This centrally located highly conserved DNA binding domain (DBD) consists of two non-repetitive globular motifs[3] where zinc is coordinated with four cysteine and no histidine residues. Their secondary and tertiary structure is distinct from that of classic zinc fingers.[4] This region controls which gene will be activated. On DNA it interacts with the hormone response element (HRE).
Hinge region: This area controls the movement of the receptor to the nucleus.
Hormone binding domain: The moderately conserved ligand-binding domain (LBD) can include a nuclear localization signal, amino-acid sequences capable of binding chaperones and parts of dimerization interfaces. Such receptors are closely related to chaperones (namely heat shock proteins hsp90 and hsp56), which are required to maintain their inactive (but receptive) cytoplasmic conformation. At the end of this domain is the C-terminal. The terminal connects the molecule to its pair in the homodimer or heterodimer. It may affect the magnitude of the response.
Mechanism of action
Genomic
Depending on their mechanism of action and subcellular distribution, nuclear receptors may be classified into at least two classes.[5][6] Nuclear receptors that bind steroid hormones are all classified as type I receptors. Only type I receptors have a heat shock protein (HSP) associated with the inactive receptor that will be released when the receptor interacts with the ligand. Type I receptors may be found in homodimer or heterodimer forms. Type II nuclear receptors have no HSP, and in contrast to the classical type I receptor are located in the cell nucleus.
Free (that is, unbound) steroids enter the cell cytoplasm and interact with their receptor. In this process heat shock protein is dissociated, and the activated receptor-ligand complex is translocated into the nucleus.
After binding to the ligand (steroid hormone), steroid receptors often form dimers. In the nucleus, the complex acts as a transcription factor, augmenting or suppressing transcription particular genes by its action on DNA.
Type II receptors are located in the nucleus. Thus, their ligands pass through the cell membrane and cytoplasm and enter the nucleus where they activate the receptor without release of HSP. The activated receptor interacts with the hormone response element and the transcription process is initiated as with type I receptors.
Non-genomic
.
Great video! But I wonder which book(/other sources) your pictures come from?
Thanks for the comment Ronja, I just chose whichever google search images I felt like were the most pedagogically effective. As far as book goes this was intended to be used for Rhodes medical physiology, I can tell you more about the book if you are interested.
Thank you so much for answering! I just wondered because we had a discussion in my class whether or not hsp are involved in both the case where the complex is built up in the cytosol and in the nucleus. As your picture shows that is the case, I wanted to ask where it comes from:)
well explained. many thanks
Thank you for being kind and leaving a comment. Be sure to ask me questions if a video doesnt explain something well enough
Nice video! So, in a Zn deficient state can that affect the overall steroid hormones from getting activated?
very good question, I am not sure if I can answer it tbh, but i found an interesting review article on the subject, www.cambridge.org/core/services/aop-cambridge-core/content/view/8229591EE15CC1CC4736DBE209A0310D/S0029665198000469a.pdf/a-role-of-zinc-in-the-regulation-of-gene-expression.pdf
@@medaphysicsrepository2639 Thank you for answering my question and the article I am about to read. The WHO, not the band but the World Health Organization, admits that 2 billion people have a gross zinc deficiency. I believe most of the world has a marginal subclinical zinc deficiency that will never be registered on any lab, but we do see hormones gone crazy. The zinc-loaded sperm is in the zinc spark of life, and yet the sperm count has decreased significantly over the last 50 years; most men are shooting blanks, and women's hormones are all over the place. Even the prophetic Simpsons, in one of their skits, "A World Without Zinc," are warning us, As we know, 1 ion of mercury can displace 1000 ions of zinc as this was proven in the mercurial diuretics back in the 1940s-50s to control Bp at the carbonic anhydrase enzyme in the kidneys. At a 1 to 1000 clip of zinc being pissed out. So my working theory is a zinc deficiency is screwing up our hormones and the P53 zinc-dependent gene, also referred to as the guardian of the genome, hence the cancers on steroids since Nixon waged war on cancer back in the 70s...
@@medaphysicsrepository2639 Thank you and for the article. In my observation and opinion, most of the world is walking around with a marginal subclinical Zn deficiency, which no current lab has the ability to detect and assess. The Zinc status, when grossly deficient, will be blatantly obvious. Even the WHO, not the band, but the World Health Organization, is letting us know that 2 billion people, primarily third world, have a gross Zn deficiency. That is about 1/3 of the world's population. Now, when the iconic Simpsons, the Nostradamus of today's popular culture, give us a skit, "A world without Zinc," that should ring the alarm bell. Zinc is under attack from many fronts as modern agriculture practices are dreadful. To the phytates, the gazillion chemicals and ubiquitous metals block zinc from absorption and through the protein channels or binding sites through ionic and molecular mimicry. This results in Zn getting displaced and blocked, with devasting effects on human physiology and psychology. Mercurial diuretics were prescribed back in the 1940s-50s for treating high BP. The mechanism of action via the Zn-dependent carbonic anhydrase enzyme in the microbe tubes of the kidneys ends up with about a thousand ions of Zn in the toilet bowl. P53, the guardian of the genome, is a Zn-dependent enzyme and is the most researched gene in cancer. Without the Zn-finger, this protein can't fold into its 3-dimensional shape to bind to the DNA binding domain on the mutated strands of DNA. We scratch our heads and wonder why cancer has skyrocketed ever since Nixon waged a war on cancer in the 1970s, creating a multi-trillion-dollar industry that is nothing short of a horrific, dismal failure. Smart money is on a toxic overload, and mineral deficiencies are the precipitating root of every chronic disease, including cancers, at least on a physical level...
I'm having trouble understanding something. At 2:29 you said that type II steroid hormones bind directly to dna or the proteins involved in expression, but at 3:38 you said that it binds to a receptor in the nucleus before binding to dna.
I am sure other students have probably been confused by that and just haven't said anything so thanks for speaking up!
I should have said "binding site" instead of receptor site, sometimes the two terms can be used interchangeably, poor choice on my part in this video (biology lacks systematic nomenclature so this stuff happens at times)
Type II binds directly to the DNA or the Proteins involved in expression, as long as you understand that you should be fine conceptually for most courses
thanks for the comment, and let me know if you have any questions. I am bored so ill probably answer it quickly
@@medaphysicsrepository2639 Thanks for the explanation Thomas
hi, ur work helped me a lot, wish u the best from France
Glad it helped
Do you know if different steroids fight for receptor binding, i.e testosterone and NPP, is it possible to saturate all the receptors or are there more receptors than one could use?
Hope you can help
Many thanks
Joel
Hi, I am not sure if i fully understand your question:
different steroids do bind to different receptors, testosterone and NPP both bind to the same receptor (type I) obviously with different affinities and different binding kinetics. Any set of receptors in biology can become saturated temporarily, usually accompanied by a response.
May I ask the context of your question?
@@medaphysicsrepository2639 I'm talking solely about anabolic steroids, I just wondered as there's a big debate that goes on regarding steroids with stronger binding affinity will obviously bind first, and testosterone with a lower affinity will be left without receptors to bind to, would this be true or would someone have to be taking a large amount of steroids to saturate the receptors with say trenbalone to then Leave testosterone without any receptors
Hope this makes sense.
Appreciate your quick response
Could you pls show animation for this pathway for better understanding
LOL dude im broke I dont have the funding to make animations, I agree that they are really helpful though, I just dont have the funding: here is one that you might like: ua-cam.com/video/m9jOXiYdMeY/v-deo.html
by 4.5 not easy to see what you write on black board
thanks for the comment as you are probably not the only one who thought that, at 4:50 the concept map in yellow is talking about the Hinge region (structurally ): this is where 1. the Nuclear localization signal (functional role: is to transport into the nucleus) ,also where HSPs dimerize if appropriate.
I"M BACK
Welcome back :)
last we spoke you were at the NIH, how is the big city life treating you ?
Hahaha, you are funny!!!
Lol You are too nice
Do you understand what you've said yourself ?
Do you have a question regarding the video ?
Not a good explanation