Transcript Receptors

Endo. 4 Detecting and signalling
Cell surface receptors: G protein linked and
tyrosine kinase receptors: second messengers,
phosphorylating kinases, activation of
transcription
Intracellular steroid receptors; transcription
factors
Receptor regulation
Hormone receptors and disease
Hormone receptors
Peptide and protein hormones
Water soluble
cell surface receptors
Activate second messengers and/or enzymes
Cytoplasmic and nuclear effects
Steroid hormones
Lipophilic
intracellular receptors in
cytoplasm or nucleus. Cell surface receptors?
Receptors are transcription factors
General types of cell surface receptors
Protein and peptide hormone
receptors
G-protein linked
Gs, Gi, Gq, G12
• Open ion channels
• Activate enzymes
second messengers
• activation of
tyrosine kinases
activation of serine/
threonine kinases
Enzyme linked or
associated
• Tyrosine kinase on
receptor or on
molecule associated
with receptor
activation of serine/
threonine kinases
G-protein linked receptors
Receptors with or associated with
tyrosine kinase domains
G-protein linked
receptors
I and E loops 1-3
Activity of trimeric G proteins after hormone
binding to a G-protein linked receptor
Second messengers in G-protein linked
receptors
• Adenyl cyclase
cAMP
Protein kinase A
DAG
• Phospholipase C
IP2
IP3
• Calcium
Protein
kinase C
Calmodulin
Ca2+
Ca-CAM
protein kinase
Signalling at the TSH
receptor
cAMP signalling
system
The
phosphinositide
signalling system
Signalling at the vasopressin receptor
A CASCADE OF KINASES
G-protein receptors
cAMP. Phospholipase C,
Ca2+/calmodulin
Protein kinase A, C, or CaCM
cytoplasm
Serine/threonine kinases
MEK
MAP pathway
nucleus
Tyrosine kinases in intracellular signalling
G-protein linked receptors
Receptors with or associated with
tyrosine kinase domains
Signalling at a receptor with tyrosine kinase activity
Insulin
Insulin signaling
in muscle
P
P
P
P
SHC
P
IRS
P
1,2,3
P
P
Endosome
GLUT-4
vesicles
PDK1
SOS
RAS
PKB
RAF, MEK, MAPK
Increased glycogen
synthase
FOS, ELK-->
gene transcription
JAK-STAT signalling
pathway - receptor with
tyrosine kinase
associated molecule
Signalling pathways at G-protein linked and tyrosine kinase receptors
STEROID RECEPTORS
Intracellular
• Type I - in cytoplasm combined with
hsp e.g sex steroids, glucocorticoids.
Form homodimers
• Type II - in nucleus, often bound to
DNA e.g. thyroid hormones,vitamin D
Form homo- and hetero-dimers
Membrane receptors
STEROID HORMONE
RECEPTORS
Steroid hormone receptors
are a family of
transcrtiption factors
Different functional regions
of the receptor are defined
as domains - A-F
The C domain is the DNA
binding region and is
highly conserved
Both the A/B domains and
E/F domains have
transcriptional activity
Different steroid receptors
are continually being
discovered
Hormone crosses cell
membrane
Heat shock protein
dissociates from
receptor
Hormone binds to
receptor and
dimerization occurs
Dimerized receptors
translocate to the
nucleus
Binds to the hormone
response element on the
DNA
Along with other
transcription factors
transcription is initiated
Steroid hormone binding to its receptor
hsp
The C domain
The DNA binding region is
made up of 2 zinc fingers
Each finger contains 3 helical
regions, I, II and III
The first helix contains the P
box which recognizes specific
base sequences on the DNA the HRE
The amino acids indicated in
brown are those concerned
with dimerization of two
receptors
Cartoon showing two dimerized receptors linking into the
DNA helix. The base sequences of the estrogen and
glucocorticoid response elements are shown below
DNA
Histones
Activation of
transcription by steroid
hormone receptors
Binding of steroid hormone
receptors (transcription factors)
to the hormone response
element on the DNA induces
chromatin remodelling
There is binding of additional
transcription factors and
acetylation of histones
RNA polymerase is activated
and transcription is stimulated
When histones are deacetylated
transcription is repressed
RECEPTOR REGULATION
• Affinity of receptors - postitive and
negative co-operativity
• Number of receptors - up and down
regulation
• Desensitization of receptors receptor phosphorylation, uncoupling
Homologous and heterologous
regulation
Receptor regulation
Phosphorylation of
receptor
Binding of arrestin
complete
desensitization
Phosphatases remove
phosphate and may
reactivate receptor
Hormone receptors and disease
• Genetic mutations of receptors - vitamin D
resistant rickets.
• Auto-antibodies against membrane receptors
- Graves’ disease.
• Inability to couple receptors with signal
transduction pathways pseudohypoparathyroidism
• Receptor regulation in excess deficiency obesity and insulin resistance
• Inappropriate receptor interaction
(specificity) - LH/TSH, prolactin/GH
Grave’s disease