Catalytic Receptors

Catalytic receptors are receptors whose activation is directly linked to enzyme activity.

The enzyme activity may be intrinsic to the receptor or associated with the receptor complex.
Receptor dimerisation is usually required for activation.

Catalytic receptors commonly bind peptide or protein ligands.

Catalytic receptor signalling is frequently involved in:

Major Classes of Catalytic Receptors:

There are two main classes of catalytic receptors.
- Receptor tyrosine kinases.
- Guanylyl cyclase receptors.
Additional catalytic receptor systems exist.
- JAK–STAT receptors recruit cytoplasmic tyrosine kinases and regulate gene transcription.
- Receptor serine/threonine kinases signal through SMAD transcription factors.

Guanylyl Cyclase Receptors and cGMP Signalling:

Guanylyl cyclase receptors regulate levels of cyclic GMP as a second messenger.

Cyclic GMP signalling parallels the cyclic AMP pathway in structure and function.
Cyclic GMP activates protein kinase G.
Cyclic GMP is degraded by phosphodiesterases, including PDE5.

Membrane-Bound Guanylyl Cyclase Receptors:

Membrane-bound guanylyl cyclase receptors respond to peptide hormones.
The GC-A receptor is activated by natriuretic peptides.
Atrial natriuretic peptide is released from the atria of the heart.
- It activates GC-A receptors in the kidney and vasculature.
  - This promotes sodium and water excretion.
    - This leads to reduced blood volume and vasodilatation.
Brain natriuretic peptide also activates GC-A receptors.
- It functions as a neuromodulator.
Uroguanylin activates GC-C receptors in the intestine.
- This stimulates epithelial secretion.
  - Pathological activation by bacterial enterotoxins causes diarrhoea.

Physiological Effects of ANP Signalling:

In vascular smooth muscle:
- Cyclic GMP signalling causes vasorelaxation.
- This leads to vasodilatation.
In the kidney:
- Cyclic GMP signalling promotes sodium and fluid excretion.
- This contributes to diuresis and natriuresis.

Gasotransmitters and Soluble Guanylyl Cyclase:

Gasotransmitters are gaseous molecules that act as signalling mediators.
- Examples include nitric oxide, carbon monoxide, and hydrogen sulphide.
Nitric oxide is a key regulator of cardiovascular function.
- It diffuses freely across membranes.
- It acts locally due to its short half-life.

Nitric Oxide and cGMP Signalling Pathway:

Nitric oxide is synthesised by nitric oxide synthase enzymes.
- Endothelial nitric oxide synthase regulates blood vessel tone.
  - Neuronal nitric oxide synthase acts as a neuromodulator.
    - Inducible nitric oxide synthase contributes to immune responses.
In endothelial cells:
- Activation of Gq-coupled GPCRs increases intracellular calcium.
  - Calcium activates endothelial nitric oxide synthase.
    - Nitric oxide is released and diffuses to nearby smooth muscle cells.
In vascular smooth muscle:
- Nitric oxide activates soluble guanylyl cyclase.
  - This increases intracellular cyclic GMP.
    - Cyclic GMP activates protein kinase G.
      - Protein kinase G induces smooth muscle relaxation.
Cyclic GMP is degraded by phosphodiesterase 5.
- This limits the duration of the signal.

Therapeutic Targeting of NO–cGMP Signalling:

Phosphodiesterase 5 inhibitors prevent cyclic GMP breakdown.
- Sildenafil is a clinically important example.
  - These drugs promote vasorelaxation and increased blood flow.
    - They are used in the treatment of erectile dysfunction and cardiovascular disease.

Receptor Tyrosine Kinases:

Overview and Ligands:

Receptor tyrosine kinases respond to growth factor ligands.
- Examples include epidermal growth factor, nerve growth factor, vascular endothelial growth factor, and insulin.
RTK activation regulates:
- Cell survival and proliferation.
- Differentiation.
- Metabolic control.
Dysregulation of RTK signalling contributes to cancer development.

Structure and Activation of RTKs:

RTKs consist of:
- An extracellular ligand-binding domain.
- A single transmembrane region.
- An intracellular tyrosine kinase domain.
Ligand binding induces receptor dimerisation.
Dimerisation activates the kinase domains.
The receptors undergo autophosphorylation on tyrosine residues.

Recruitment of Signalling Proteins:

Phosphorylated tyrosine residues act as docking sites.
Signalling proteins bind via SH2 domains.
- SH2 domains recognise phosphotyrosine and surrounding residues.
- This confers signalling specificity.
Different RTKs generate distinct phosphotyrosine patterns.
- This recruits different combinations of signalling proteins.

RTK Signalling via PLCγ and Calcium:

Phospholipase C gamma is recruited via its SH2 domain.

PLCγ hydrolyses phosphatidylinositol 4,5-bisphosphate.
- This generates inositol 1,4,5-trisphosphate and diacylglycerol.
  - Inositol 1,4,5-trisphosphate releases calcium from the endoplasmic reticulum.
    - Diacylglycerol and calcium activate protein kinase C.
      - This pathway links RTK activation to calcium signalling and PKC activation.

RTK Signalling via the Ras–MAP Kinase Pathway:

Some SH2-containing proteins act as adaptor proteins.
- Grb2 is a key adaptor linking RTKs to Ras activation.
Ras is a small monomeric G protein.
- Ras–GTP is the active form.
- Ras–GDP is the inactive form.
Guanine nucleotide exchange factors promote GDP–GTP exchange.
GTPase-activating proteins enhance Ras GTP hydrolysis.
Activated Ras initiates a kinase cascade.
- Raf phosphorylates MEK.
- MEK phosphorylates MAP kinase.
MAP kinase regulates:
- Cytoplasmic proteins involved in translation.
- Nuclear transcription factors controlling gene expression.

RTK Signalling and Cancer:

Mutations in RTKs or downstream signalling proteins act as oncogenes.
- Mutated Ras is present in approximately 20 percent of human cancers.
  - HER2 receptor overexpression occurs in some breast cancers.
    - Constitutive activation of RTK pathways promotes uncontrolled proliferation and survival.

Therapeutic Targeting of RTKs:

Antibody-Based Therapies:

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Small-Molecule Kinase Inhibitors: