1. Protein Receptors & Signal Transduction
Dr Sufyan Akram

2. Lecture outline Introduction to Signal transduction pathways
Cellular receptors
Cell surface receptors
G protein coupled receptors
Tyrosine kinase receptors
Intracellular Receptors

3. Control systems of the body
Human body has thousands of control systems in it
Nervous System
Hormones
Complex, interconnected control mechanisms
Organs/
Systems
e.g. Pancreas (blood glucose sensing and release of Insulin)
Tissues
Tissue factors
Cells
Genetic control

4. Autocrine
Paracrine
Endocrine

5. What are hormones
Endocrine hormones are secreted by specialized glands/tissues
Carried by blood to cells throughout the body
Some have general effects, while others only affect specific target organs
Hormonal effects on target cells depend upon presence of specific receptors

6. General Mechanism of Hormone Action
Specificity of Hormone and Target Tissue interaction is dependent upon the location of cellular receptors:
Plasma membrane of cells (surface receptors)
In the cytosol or nucleus (intra-cellular receptors)

7. Hormone Receptors
The interaction is swift and reversible, allowing rapid onset and termination of hormone action
Receptor affinity for hormone must be high as hormones circulate in pico- or nanomole concentrations
Receptors are also specific

8. What are Receptors? Usually proteins or glycoproteins
Ligand-receptor interaction brings about conformational change in the receptor leading to activation of intracellular mediators (“second messengers”)
Second messengers, would then activate further molecules in the cell…

9. Two major types of Receptors

10. Cell surface receptors

14. Activation of downstream target molecules   
Ligand
Adenylyl cyclase
Receptor
GTP Gs
GDP
GTP
ATP
cAMP
Activation of downstream target molecules   
Intracellular effects
G-proteins could be stimulatory (Gs) or inhibitory (Gi)
Each hormone receptor interacts specifically with either Gs or Gi

15. cAMP
Cyclic adenosine monophosphate (cAMP) is a nucleotide generated from ATP through the action of the enzyme adenylate cyclase
The intracellular concentration of cAMP is increased or decreased by activation of a variety of receptors
cAMP activates a large number of downstream targets

16. cAMP
Protein kinase A is normally in a catalytically-inactive state, but becomes active when it binds to cAMP
Upon activation, protein kinase A phosphorylates a number of other proteins
Levels of cAMP decrease due to destruction by cAMP-phosphodiesterase and the inactivation of adenylate cyclase

17. RTK
The receptors for several protein hormones are themselves protein kinases which are switched on by binding of hormone. The kinase activity associated with such receptors results in phosphorylation of tyrosine residues on other proteins
Insulin is an example of a hormone whose receptor is a tyrosine kinase

18. RTK
The hormone binds to domains exposed on the cell's surface, resulting in a conformational change that activates kinase domains located in the cytoplasmic regions of the receptor
In many cases, the receptor phosphorylates itself as part of the kinase activation process
The activated receptor phosphorylates a variety of intracellular targets, many of which are enzymes

19. 2nd Messenger Systems Second Messenger Examples of Hormones Cyclic AMP
Epinephrine and norepinephrine, glucagon, LH, FSH, TSH, calcitonin, PTH, ADH
Receptor Tyrosine Kinase
Insulin, GH, PRL, Oxytocin, erythropoietin, several growth factors
Calcium and / or Phosphoinositides
Epinephrine and norepinephrine, angiotensin II, ADH, GRH, TRH
Cyclic GMP
ANP, nitric oxide

20. Insulin-RTK Receptor (an example)

21. Insulin Insulin is a hormone associated with energy abundance
In the case of excess carbohydrates, it causes them to be stored as glycogen mainly in the liver and muscles
Excess carbohydrates that cannot be stored as glycogen are converted into fats and stored in the adipose tissue
In the case of proteins, insulin has a direct effect in promoting amino acid uptake by cells

22. Insulin
To initiate its effects on target cells, insulin first binds with and activates a membrane receptor protein (RTK)

23. IRS (Insulin Receptor Substrates) Phosphorylation of Enzymesα α
Glucose
Insulin Receptor
-S-S-
S-S-
-S-S
GLUT β β P P
IRS (Insulin Receptor Substrates)
Phosphorylation of Enzymes
Glucose Transport
Glucose Synthesis
Fat Synthesis
Protein Synthesis
Transcription of Target Genes

24. Intracellular receptors

25. Intracellular Receptors
Steroid and thyroid hormone receptors are members of a large group ("superfamily") of transcription factors. All of these receptors are composed of a single polypeptide chain that has three distinct domains

26. Intracellular Receptors
The amino-terminus: this region is involved in activating or stimulating transcription by interacting with other components of the transcriptional machinery.
DNA binding domain: Amino acids in this region are responsible for binding of the receptor to specific sequences of DNA.
The carboxy-terminus or ligand-binding domain: This is the region that binds hormone

27. Hormone-Receptor Binding and Interactions with DNA
Being lipids, steroid hormones enter the cell by simple diffusion across the plasma membrane. Thyroid hormones enter the cell by facilitated diffusion
The receptors exist either in the cytoplasm or nucleus, which is where they meet the hormone. When hormone binds to receptor, a characteristic series of events occurs…

29. Receptor activation is the term used to describe conformational changes in the receptor induced by binding hormone. The major consequence of activation is that the receptor becomes competent to bind DNA
Activated receptors bind to hormone response elements, which are short specific sequences of DNA which are located in promoters of hormone-responsive genes
Most commonly, receptor binding to DNA stimulates transcription. The hormone-receptor complex thus functions as a transcription factor

30. In Summary
Receptors are specific proteins which can be activated by various factors (ligands)
Once activated, the receptors activate further molecules leading to a chain of events (signaling cascade)
The effects could be immediate (like changes in membrane permeability to certain ions) or long-term (like transcription of genes)

31. Thank you for paying attention