IV Cell Signalling

Many chemical messengers or extracellular signaling molecules have receptors inside target cells, known as intracellular receptors.
These receptors are for lipophilic messengers, usually located in the cytosol or nucleus.
Lipophilic messengers are soluble in lipids and hydrophobic.
Their solubility increases by binding to carrier proteins for transport in the blood.
They dissociate from plasma proteins before binding to the receptor and have longer half-lives than other messengers because they are transported bound to plasma proteins.

Steroid Hormones: Derived from cholesterol; synthesised by specific endocrine cells.
- Examples: Cortisol, Vitamin D, Steroid sex hormones
- Progesterone: Synthesised by the ovary and placenta, involved in the development of the uterus.
- Oestrogen: Involved in the development of female sexual characteristics.
- Testosterone: Produced in the testes, responsible for the development of male sexual characteristics and hair growth.
Cortisol (Glucocorticoid):
- Secreted from the cortex of the adrenal gland.
- Controls the metabolic rate of many cells.
Vitamin D:
- Synthesized in the skin upon light exposure and activated in the liver and kidney to form calcitriol.
- Calcitriol is responsible for calcium homeostasis.
Thyroid Hormones:
- Derived from the amino acid tyrosine.
- Affect the metabolism of many cells and regulate metabolism.
Retinoids:
- Derived from vitamin A (retinol).
- Involved in the synthesis of lipophilic hormones and alter gene expression.
Most act by changing gene expression.

Cholesterol is the precursor for steroid hormones.
Progesterone is derived from cholesterol and is a precursor to corticosteroids, aldosterone, and cortisol.

Cytoplasmic Receptors:
- Located in the cytoplasm.
- Upon ligand binding, the complex translocates to the nucleus through the nuclear pore.
- Affects gene expression.
- Example: Cortisol receptor.
Nuclear Receptors:
- Located in the nucleus.
- Chemical messenger diffuses to the nucleus to bind to these receptors.
- Steroid Hormone Receptors are receptors for steroid hormones and were the first identified to affect gene expression.
- Non-Steroid Receptors are receptors for non-steroid compounds like retinoid acid, vitamin A, thyroid hormone, and vitamin D.
- These ligands act as transcription factors affecting gene expression.
Orphan Nuclear Receptors:
- Structurally related to nuclear receptors.
- Identified by DNA sequencing, but their ligands have not yet been identified.

All share a DNA binding domain.
Act as transcription factors, binding to DNA to either promote or inhibit gene expression.
The DNA binding domain is characteristic of transcription factors.

DNA binding domain:
- Around 60 amino acids.
- Flanked by the C-terminal regulatory domain
AMD Domain:
- Located at the N-terminal.
- Variable region between 50 to over 500 amino acids; contains the activation function one (AF1).
Ligand binding domain:
- Between 200 to 250 amino acids.
- Responsible for association with heat shock proteins regulating receptor activity.
Nuclear Localisation Sequence (NLS):
- Responsible for localisation of these receptors to the nucleus.

Central DNA binding domain flanked by the C-terminal and the ligand binding domain.
Transactivation domain AF1 positioned at the N-terminal.
Transactivation domain AF2 overlaps with the ligand binding domain.
- Responsible for receptor dimerisation.
AF1 and AF2 recruit transcriptional co-activators.
DNA binding domain contains two zinc finger sequences.
- Each consists of approximately 66 amino acids.
- Cysteine binds to zinc.
- Proteins with zinc finger domains can bind DNA and regulate gene expression.
Nuclear localisation signal is located in the center within the ligand binding site.

Lipophilic ligands cross the cell membrane.
Receptors are in the cytoplasm.
Ligand binding causes the receptor to dimerise.
The ligand-receptor complex translocates to the nucleus.
Recognises a hormone-responsive element on DNA to drive transcription.
Ligand penetrates the cell membrane and binds to receptors in the cytoplasm.
The binding activates the receptors, leading to dimerisation and translocation to the nucleus.
In the nucleus, the complex binds to the hormone-responsive element on DNA, acting as a transcription factor.
Some are found in the cytoplasm bound to heat shock proteins (e.g., HSP70, HSP50, and HSP90) in an inactive complex.
Ligand binding causes the dissociation of heat shock proteins.
The ligand-receptor complex can then enter the nucleus and bind to the hormone-responsive element.
The hormone-responsive element is a specific DNA sequence recognised by the ligand-receptor complex.

Lipophilic messengers enter the cell membrane by diffusion.
If receptors are in the nucleus, the messenger diffuses to the nucleus to bind.
If the receptor is cytoplasmic, the ligand binds to the cytoplasmic receptors, forming a ligand-receptor complex that enters the nucleus.
The hormone-receptor complex binds to the hormone-responsive element on DNA, driving transcription.
Transcription synthesises messenger RNA (mRNA).
mRNA leaves the nucleus via nuclear pores.
mRNA is translated into protein by ribosomes in the cytoplasm.

If a receptor is in the nucleus, the hormone diffuses into the nucleus and binds, forming a hormone-receptor complex.
If a receptor is in the cytosol, the hormone binds there, forming a hormone-receptor complex that enters the nucleus.
Inside the nucleus, the hormone-receptor complex binds to the hormone-responsive element located on a specific gene.
Binding activates or deactivates gene transcription.
Activation of gene transcription results in mRNA synthesis, which is then moved out of the nucleus into the cytosol where it is translated to a protein by ribosomes.