Signal Transduction 4

What are the four major types of membrane-bound receptors

1. Ion channel–enclosing receptors

2. 7-transmembrane (GPCRs)

3. 1 Hydrophobic domain Single-pass receptors with enzymatic activity (e.g., RTKs)

4. 1 Hydrophobic domain Single-pass receptors without enzymatic activity (e.g., cytokine receptors → Jak/STAT).

What do cytokines typically induce in target cells

Complex cellular programmes, usually driven by activation of transcriptional programmes.

What does STAT stand for

Signal Transducer and Activator of Transcription.

What does JAK stand for

Janus Kinase.

How does cytokine receptor and RTK signalling overlap

Both can activate:

• PI3K pathway

• PLC-γ (gamma) pathway

• Ras & MAPK (mitogen activated protein kinase) pathway.

What is unique about many cytokines compared to RTKs

They also directly activate STAT transcription factors via the JAK-STAT pathway.

Which receptors regulate angiogenesis

Both cytokine receptors and RTKs

What causes abnormal vascularisation in tumours

Dysregulated signalling by angiogenic factors

How are signal transduction pathways grouped

By the type of receptor:

• Membrane-bound receptors (ion channels, GPCRs, RTKs, cytokine receptors)

• Cytosolic receptors

• Nuclear receptors.

What type of ligands are required for intracellular receptors

Membrane-permeable molecules (steroid hormones, lipophilic vitamins, small molecules like NO and H₂O₂).

What % of marketed drugs target intracellular receptors

About 10–15%.

Give an example of drugs that target intracellular receptors

Steroid drugs.

What type of receptor is the soluble guanylate cyclase receptor

Cytosolic

What is the ligand for soluble guanylate cyclase receptors

Nitric oxide (NO).

How is NO produced in the body

In endothelial cels by nitric oxide synthase (NOS) enzymes from the amino acid arginine.

Physiological functions of NO

• Smooth muscle relaxation

• Platelet aggregation regulation

• Neurotransmission.

Why is NO suitable as a ligand for cytosolic receptors such as cytosolic guanylate cyclase receptors

It is small, lipophilic, and diffuses easily across membranes.

What is the enzymatic activity of cytosolic guanylate cyclase

Converts GTP into cGMP (cyclic GMP)

Where & by what is NO produced

Endothelial cells, neuronal cells, macrophages.

By a group of enzymes called nitric oxide synthases (NOS)

Name 3 types (isoforms) of nitric oxide synthases (NOS)

• neuronal NOS (nNOS)

• endothelial NOS (eNOS)

• inducible NOS (iNOS)

What regulates NO synthesis

• Intracellular Ca²⁺ levels (for eNOS, nNOS).

• Regulating the synthesis of NOS on gene level (iNOS)

What are the downstream components of sGC signalling

1. NOS (nitric oxide synthase) produces NO from arginine

2. NO binds to sGC (soluble guanylate cyclase)

3. sGC (soluble guanylate cyclase) converts GTP to cGMP

4. cGMP activates PKG (protein kinase G)

5. PKG causes smooth muscle relaxation by decreasing intracellular Ca²⁺ & activating myosin light chain phosphatase (MLCP)

What stops the smooth muscle relaxation caused by Soluble guanylate cyclase-induced signalling

PDE degrades cGMP → GMP thereby switching off the signal downstream.

What are the biological effects of cGMP signalling

• Smooth muscle relaxation (vasodilation)
• Inhibition of platelet aggregation
• Modulation of neurotransmission.

What would be the amplification systems for RTKs be

cGMP

PKG

What are nuclear receptors

Transcription factors activated by small, lipophilic ligands.

Examples of Class I nuclear receptors (steroid family)

• Progesterone receptor

• Oestrogen receptor

• Glucocorticoid receptor

• Androgen receptor

• Mineralocorticoid receptor.

Where are Class I nuclear receptors located when inactive

In the cytosol, bound to heat shock proteins (HSPs).

What happens when a steroid hormone binds to a class I nuclear receptor

1. HSPs (heat shock proteins) dissociate.

2. Receptor dimerizes.

3. It translocates to the nucleus.

4. In the nucleus it binds to hormone response elements (HREs) on DNA.

5. Recruits proteins, including RNA polymerase to the NR/DNA complex  (NR = nuclear receptor) → transcribes DNA → mRNA → biological response.

Where are Class II nuclear receptors located

Retained in the nucleus, even when no ligand is bound (when it is inactive)

What happens when a ligand binds to a class II nuclear receptor

1. Corepressor proteins dissociate.

2. Coactivator proteins are recruited.

3. Recruits proteins, including RNA polymerase to the NR/DNA complex  (NR = nuclear receptor) → transcribes DNA → mRNA → biological response

Examples of Class II nuclear receptors

• Retinoic acid receptor

• Retinoid X receptor

• Thyroid hormone receptor

• Vitamin D receptor (VDR)

• Peroxisome proliferator-activated receptor (PPAR).

Learning outcomes

also:

Signalling via nuclear receptors

1. The signal (suitability of the signal for nuclear receptor, examples)

2. The receptor (cellular localisation, function (transcription factor), regulation (HSPs,

corepressors)

3. Type 1 vs type 2 pathway