Pharmacology - Catalytic & Nuclear Receptors Flashcards
What are catalytic receptors made out of?
cell-surface proteins, usually dimeric in nature, which encompass ligand binding and functional domains typically in one polypeptide chain
What does dimerisation lead to?
activation
Define dimerisation in receptor:
a general mechanism to increase binding site affinity, specificity, and diversity
RTK
Receptor Tyrosine Kinase
Name Receptors for growth factors:
Epidermal growth factor- EGF
Vascular endothelial growth factor-VEGF
Insulin
Neurotrophins
Insulin-like growth factor- IGF
Platelet-derived growth factor- PDGF
& many others
What does activation of receptor lead to?
cell proliferation, differentiation, survival and metabolism
What doe HYPERactivation lead to?
to polyps, tumour and cancer
Growth factor binding RTK, leads
dimerization and autophosphorylation
One tyrosine kinase ______ autophosphorylation of its partner and vice versa
activate
- Signalling proteins recruited to RTK
- Signalling proteins contains SH2 domain to sense and bind specific RTK (specificity)
once ligand binds to receptor [extracellular] =
dimerisation > autophosphorylation > activation of downstream signalling [mostly intracellular]
Some SH2 domain proteins are enzymes
directly produce signals: e.g. phospholipase C- activation leads intracellular
Some SH2 domain proteins are adaptors
They link the RTK with the signalling protein
-e.g. Grb2 links between EGF receptor and SOS, a regulator of the Ras-MAP kinase pathway (will learn Ras-MAP kinase in details in the progressive years)
Signal 1
proliferation
Signal 2
Survival
Receptor Tyrosine Kinase (RTK)- drugs
Very limited
Insulin: life saving drug (in PCL III, revisit insulin’s RTK signalling
Many neurotrophin analogues couldn’t pass through clinical trials (failures)
Monoclonal antibodies
What are Guanynyl cyclase receptors? (Limited membrane bound)
single-pass transmembrane proteins activated by low intracellular calcium levels and inhibited by high intracellular calcium levels
e.g- atrial natriuretic peptide
(recollect CVS lecture 5)
-released from atria, promotes vasodilation and urinary sodium excretion
When ligand binds to receptor [Atrial natriuretic peptide] what does GTP form?
GTP > cGMP > PK g > vasodilation
Guanynyl cyclase receptors – cytoplasmic-Nitric oxide
Nitric oxide (NO)
- endothelium derived vasodilator factor (gasotransmitters)
Vascular Smooth muscle:
- NO stimulates cytoplasmic guanylyl cyclase
- Elevation of intracellular [cGMP]
- Activation of protein kinase G
- Smooth muscle relaxation
- PDE isoform breaks down cGMP
Cytoplasmic & Nuclear receptors
Intracellular receptors & transcription factors
Ligands diffuse across membranes to intracellular receptors
Steroidal hormonal function
Oestrogen act of Oestrogen receptor
Drug: Tamoxifen
used for which coindition?
breast cancer
Intracellular receptors & transcription factors
Ligands _____ across membranes to intracellular receptors
diffuse
Peroxisome proliferator-activated receptors (PPARs)- transcription factor
Drugs- Glitazones (anti-diabetic)
Journey of intracellular receptors and hormones:
hormone > cytosolic receptor > diffusion into nucleus/ nuclear receptor > DNA to mRNA > specific proteins > biological effects
