Endo. 4 Detecting and signalling Cell surface receptors: G protein linked and tyrosine kinase receptors: second messengers, phosphorylating kinases, activation.
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Endo. 4 Detecting and signalling
Cell surface receptors: G protein linked and tyrosine kinase receptors: second messengers, phosphorylating kinases, activation of transcriptionIntracellular steroid receptors; transcription factorsReceptor regulationHormone receptors and disease
Hormone receptorsHormone 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
Protein and peptide hormone receptors
G-protein linked
Gs, Gi, Gq, G12
• Open ion channels
• Activate enzymessecond messengers• activation of
tyrosine kinases activation of serine/
threonine kinases
Enzyme linked or associated
• Tyrosine kinase on
receptor or on
molecule associated
with receptoractivation of serine/threonine kinases
Second messengers in G-protein linked receptors
• Adenyl cyclase cAMP Protein kinase A
DAG Protein kinase C
• Phospholipase C IP2
IP3 Ca2+
• Calcium Calmodulin Ca-CAM protein kinase
A CASCADE OF KINASESG-protein receptors
cAMP. Phospholipase C, Ca2+/calmodulin
Protein kinase A, C, or CaCM cytoplasm
Serine/threonine kinases
MEK MAP pathway nucleus
IRS1,2,3
P
P
P
P
PP
Insulin
PI3K
PDK1
Increased glycogen synthase
PKB
GLUT-4vesicles
GRB/SHP
SOS
RAS
RAF, MEK, MAPK
FOS, ELK--> gene transcription
SHCP
Endosome
Insulin signaling
in muscle
P
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
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
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
HistonesDNA
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 regulationPhosphorylation 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
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