Download Receptors Functions and Signal Transduction- L4

Receptors Functions and Signal
Transduction- L4- L5
Faisal I. Mohammed, MD, PhD
University of Jordan
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PLC- signaling pathway
PKC
Phosphorylates
many substrates,
can activate
kinase pathway,
gene regulation
 Receptors superfamilies:
Ionotropic receptors (ligand-gated channels)
Metabotropic receptors (G protein-coupled receptors)
Tyrosine Kinase
Almost all neurotransmitters discovered so far have more
than one kind of receptor -- called receptor subtypes.
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Blood capillary
1 Binding of hormone (first messenger)
to its receptor activates G protein,
which activates adenylate cyclase
Water-soluble
hormone
Adenylate cyclase
Receptor
Second messenger
G protein
ATP
cAMP
2 Activated adenylate
cyclase converts
ATP to cAMP
Protein kinases
6 Phosphodiesterase
inactivates cAMP
3 cAMP serves as a
second messenger
to activate protein
kinases
Activated
protein
kinases
4 Activated protein
Protein
kinases
phosphorylate
cellular proteins
ATP
ADP
Water-soluble
Hormones
Protein— P
5 Millions of phosphorylated
proteins cause reactions that
produce physiological responses
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Target cell
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Cyclic Monophasphate (cAMP) Second Messenger
Mechanism
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Cell Membrane Phospholipid Second Messenger
System
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Epinephrine Can Act Through Two 2nd
Messenger Systems
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Free hormone
Blood capillary
1 Lipid-soluble
Transport
protein
hormone
diffuses into cell
2 Activated
Nucleus
Receptor
receptor-hormone
complex alters
gene expression
DNA
Cytosol
mRNA
3 Newly formed
mRNA directs
synthesis of
specific proteins
on ribosomes
Ribosome
New
protein
4 New proteins alter
Lipid-soluble
Hormones
cell's activity
Target cell
Hormones That Bind to Nuclear Receptor
Proteins


Lipophilic steroid and
thyroid hormones are
attached to plasma
carrier proteins.
 Hormones dissociate
from carrier proteins
to pass through lipid
component of the
target plasma
membrane.
Receptors for the
lipophilic hormones are
known as nuclear
hormone receptors.
Nuclear Hormone Receptors




Steroid receptors are located in cytoplasm and in the
nucleus.
Function within cell to activate genetic transcription.
 Messenger RNA directs synthesis of specific
enzyme proteins that change metabolism.
Each nuclear hormone receptor has 2 regions:
 A ligand (hormone)-binding domain.
 DNA-binding domain.
Receptor must be activated by binding to hormone
before binding to specific region of DNA called HRE
(hormone responsive element).
 Located adjacent to gene that will be transcribed.
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Mechanisms of Steroid Hormone Action





Cytoplasmic receptor
binds to steroid hormone.
Translocates to nucleus.
DNA-binding domain
binds to specific HRE of
the DNA.
Dimerization occurs.
 Process of 2 receptor
units coming together at
the 2 half-sites.
Stimulates transcription of
particular genes.
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Mechanism of Thyroid Hormone Action


T4 passes into cytoplasm and is
converted to T3.
Receptor proteins located in
nucleus.
 T3 binds to ligand-binding
domain.
 Other half-site is vitamin A
derivative (9-cis-retinoic)
acid.


DNA-binding domain
can then bind to the halfsite of the HRE.
Two partners can bind to the
DNA to activate HRE.

Stimulate transcription
of genes.
Steroid & Thyroid Hormones - Mechanism of
Action
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Actions of Thyroid Hormones
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Determinants of Free Hormone Receptor
Binding
Carrier-bound
hormone
Endocrine
cell
Free
Hormone
Hormone
receptor
Hormone
degradation
Biological
effects
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Correlation of Plasma Half-Life & Metabolic Clearance
of Hormones with Degree of Protein Binding
Hormone
Protein
Plasma half-life
binding (%)
Metabolic clearance
(ml/minute)
Thyroid
Thyroxine
Triiodothyronine
99.97
99.7
6 days
1 day
Steroids
Cortisol
Testosterone
Aldosterone
94
89
15
100 min
85 min
25 min
140
860
1100
Proteins
Thyrotropin
Insulin
Antidiuretic hormone
little
little
little
50 min
8 min
8 min
50
800
600
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0.7
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Circulating Transport Proteins
Principle Hormone
Transported
Transport Protein
Specific
Cortisol, aldosterone
Corticosteroid binding globulin
(CBG, transcortin)
Thyroxine binding globulin (TBG) Thyroxine, triiodothyronine
Testosterone, estrogen
Sex hormone-binding globulin
(SHBG)
Nonspecific
Albumin
Transthyretin (prealbumin)
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Most steroids, thyroxine,
triiodothyronine
Thyroxine, some steroids
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Feedback Mechanisms
Positive Feedback
Negative Feedback
+
+
Endocrine
cell
_
Target
cell
Endocrine
cell
Target
cell
+
Biological effects
Biological effects
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Steroid & Thyroid Hormones - Receptors
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Enzyme-linked
Receptor (the
Leptin receptor)
JAK= Janus
Kinase
STAT= Signal
Transducer
and Activator
of Transcription
Tyrosine Kinase
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Tyrosine Kinase Receptors:
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Tyrosine Kinase



Insulin receptor consists of 2 units that dimerize
when they bind with insulin.
 Insulin binds to ligand–binding site on plasma
membrane, activating enzymatic site in the
cytoplasm.
Autophosphorylation occurs, increasing tyrosine
kinase activity.
Activates signaling molecules.
 Stimulate glycogen, fat and protein synthesis.
 Stimulate insertion of GLUT-4 carrier proteins.
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Tyrosine Kinase
(continued)
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The Insulin Receptor & Mechanisms
of Insulin Action
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Insulin Action on Cells:
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Signaling molecule
(hormones)
Receptor of target cell
Signal
transduction
Intracellular molecule
(second messengers)
biological effect
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Third messengers:
Third messengers are the molecules which
transmit message from outside to inside of
nucleous or from inside to outside of nucleous,
also called DNA binding protein.
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Proteins and peptides:
Effect by
membrane
receptors
Extracellular
molecules
Effect by
intracellular
receptors
Signal
molecules
Intracellular
molecules
Hormones, cytokines
Amino acid derivatives:
Catecholamines
Fatty acid derivatives:
Prostaglandins
Steroid hormones,
Thyroxine, VD3
cAMP, cGMP, IP3, DG, Ca2+
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