Lecture notes
Steriod Hormone Signalling
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- Aston University, Birmingham (Aston)
In depth cell signalling and physiology notes, created using synchronous and asynchronous material.
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Steroid hormone signalling.Mechanisms of hormone action.
All hormone action is receptor mediated.
A hormone needs to bind to a receptor to elicit a physiological and cellular response.
Peptide hormones:
Receptor sits in the cell membrane.
Ligand binds to the receptor and that signal is transduced across the membrane into
the cell.
Steroid hormones:
Steroid hormones, because of their structure, can cross the hydrophobic
environment, of the lipid bilayer.
Their receptor sits inside the cell.
The signaling mechanisms are different between the two.
Amino acid hormones (3rd class of hormones)
Amino acid hormones can have cell surface receptors, or like in the case of thyroid
hormone, the receptor is in the cell
Structure of steroid hormones.
All steroid hormones have a similar underlying structure.
Steroid hormones have a sterane structure.
This structure consists of 4 cyclic compounds with an androstane skeleton, and they
differ by a side chain (0H in this case) which is attached to the 17 th carbon.
Because of this structure, the steroid hormones are all lipophilic, which means that
they are lipid soluble.
Steroid hormone synthesis.
All steroid hormones are made from the same precursor molecule, cholesterol.
The first step of the process is to strip back the cholesterol structure at the side
chain on the carbon 17, to make a generic sterane structure.
Where does the cholesterol comes from?
Cholestrol for steroid hormone synthesis comes from 2 major sources:
The first is de novo synthesis.
Here cholesterol is generated from acetyl coA through a series of biochemical steps
to form HMG-coA, which is then converted to mevalonate, which is then converted
to cholesterol.
The rate limiting step of cholesterol synthesis occurs between the first two
molecules and is mediated by the enzyme HMG-CoA reductase.
Cholesterol can negatively regulate its own production, through negative feedback
back to the biosynthetic step (between the first and second molecule).
Cholesterol can also come from the breakdown of LDL.
LDL is a major way of transporting lipids in the circulation.
In the LDL droplet we have this outer layer of phospholipids and then this inner core
of cholesterol along with triglycerides and cholesterol esters.
, The breakdown of these LDL molecules can release cholesterol for use in steroid
hormone synthesis.
Steroid hormone biosynthesis.
The biosynthesis of steroid hormones happens within the mitochondria in the cell.
It involves a number of enzymes.
First step of this biosynthetic pathway is the conversion of cholesterol to
pregnenolone.
This involves the activity of two enzymes, cholesteroldesmolase and cytochrome
p450.
Cholesterol is transported to the mitochondria and then this C17 side chain is
cleaved.
And the cleavage event forms the pregnenolone.
The steroidogenic pathway.
Cholestrol is at the top as a parent molecule
And there are the 3 layers of the adrenal cortex: zona fasciculata, zona glomerulosa,
zona reticularis.
Within each layer of the adrenal cortex we have different biosynthetic pathways that
will generate different species of steroid hormone.
Different regions of the adrenal cortex generate different steroid hormones.
The reason they generate different hormones is because the enzymes they generate
in these different biosynthetic pathways are expressed differently in these different
regions of the adrenal gland.
All steroid hormones start with cholesterol, they all have the same first step of the
biosynthetic pathway, which is the formation of pregnelalone.
Hormonal stimulation of steroidogenesis.
Process of steroid hormone biosynthesis is hormonally regulated.
Example of this is the regulation of cortisol synthesis, by the hormone ACTH.
Diagram shows the steps in a cell signaling pathway, that utilizes cell surface
receptor.
Receptor in purple, ligand binding domain is positioned outside the cell
extracellularly.
There are then multiple proteins within the cell that will be involved in transduction
of that extracellular ligand.
Proteins include things like intracellular mediators, adaptor proteins, docking
proteins, GTP binding proteins, which we have seen in other signaling pathways.
May include effector enzymes, certain protein or lipid kinases, as well as target
proteins, those cellular proteins that are going to elicit the change in cell behavior or
produce that cellular response to the ligand.
You can also see second messengers as well as small molecules.
We can map any signal transduction pathway that uses a cell surface receptor onto
this basic scheme.
Steroid hormone release and transport.
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