1. 11.2 Reception: A signaling molecule binds to a receptor protein, causing it to change shape
A receptor protein on or in the target cell allows the cell to “hear” the signal and respond to it.
The binding between a signal molecule (ligand) and receptor is highly specific.
Response to ligand binding:
A shape change in a receptor, which directly activates the receptor.
Aggregation of two or more receptor molecules.
Most signal receptors are plasma membrane proteins.

2. Receptors in the Plasma Membrane
Most water-soluble signal molecules bind to specific sites on transmembrane receptor proteins that transmit information from the extracellular environment to the inside of the cell.
There are three main types of membrane receptors:
G protein-coupled receptors
Receptor tyrosine kinases
Ion channel receptors
2-adrenergic receptors
Molecule resembling ligand
Plasma membrane
Cholesterol

3. G Protein-Coupled Receptors (GPCR)
G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors.
A GPCR is a plasma membrane receptor that works with the help of a G protein (protein that binds GTP).
The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive.
Receptors vary in the binding sites for their signaling molecules and also for different types of G proteins inside the cell.
GPCR proteins are all similar in structure.
7 transmembrane alpha helices
Loops between helices form binding sites for signaling molecules and G proteins.
Malfunctions of G proteins are involved in bacterial infections.
Examples: cholera and pertussis
Bacterial toxins interfere with G protein function.
Signaling molecule binding site
Segment that interacts with G proteins
G protein-coupled receptor

4. G protein-coupled receptor Plasma membrane Activated receptor
Figure 11.7b
G protein-coupled receptor
Plasma membrane
Activated receptor
Signaling molecule
Inactive enzyme
GTP
GDP
GDP
CYTOPLASM
G protein (inactive)
Enzyme
GTP 1 2
GDP
Activated enzyme
Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors
GTP
GDP
P i 3
Cellular response 4

5. Receptor-tyrosine kinases (RTKs)
RTKs are membrane receptors that attach phosphates to tyrosines.
The cytoplasmic part of the receptor functions as the tyrosine kinase.
A receptor tyrosine kinase can trigger multiple signal transduction pathways at once.
Abnormal functioning of RTKs is associated with many types of cancers.
Breast cancer patients may have high levels of HER2 (RTK).
A protein called Herceptin can bind to HER2 and inhibit cell division.

6. Signaling molecule (ligand) Ligand-binding site
Figure 11.7c
Signaling molecule (ligand)
Ligand-binding site
 helix in the membrane
Signaling molecule
Tyrosines
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
CYTOPLASM
Receptor tyrosine kinase proteins (inactive monomers)
Dimer 1 2
Activated relay proteins
Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors
Cellular response 1
Tyr
Tyr P
Tyr
Tyr P
Tyr
Tyr P P
Tyr
Tyr P
Tyr
Tyr P
Tyr
Tyr P P
Cellular response 2
Tyr
Tyr P
Tyr
Tyr P
Tyr
Tyr P
6 ATP
6 ADP P
Activated tyrosine kinase regions (unphosphorylated dimer)
Fully activated receptor tyrosine kinase (phosphorylated dimer)
Inactive relay proteins 3 4

7. Ion Channel Receptors
A ligand-gated ion channel receptor acts as a gate when the receptor changes shape.
When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor.
Ion channel receptors are very important in the nervous system. 1 2 3
Gate closed
Ions
Gate open
Gate closed
Signaling molecule (ligand)
Plasma membrane
Ligand-gated ion channel receptor
Cellular response

8. Intracellular Receptors
Hormone (aldosterone)
EXTRACELLULAR FLUID
Intracellular Receptors
Intracellular receptor proteins are found in the cytosol or nucleus of target cells.
Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors.
Examples of hydrophobic messengers are the steroid and thyroid hormones of animals.
Once a hormonse has entered the cell, it may bind to an intracellular receptor in the cytoplasm or the nucleus.
The binding changes the receptor into a hormone- receptor complex that is able to cause a response.
Plasma membrane
Receptor protein
Hormone- receptor complex
DNA
mRNA
NUCLEUS
New protein
CYTOPLASM

9. Concept Check
Nerve growth factor (NGF) is a water-soluble signaling molecule. Would you expect the receptor for NGF to be intracellular or in the plasma membrane? Why?
What would the effect be if a cell made defective receptor tyrosine kinase proteins that were unable to dimerize?
How is ligand binding similar to the process of allosteric regulation of enzymes?

10. 11.3 Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell
Signal transduction usually involves multiple steps and molecules.
Steps often include activation of proteins by addition or removal of phosphate groups or release of other small molecules or ions.
Benefits of multistep pathways:
Amplification of response
More opportunities for coordination and regulation

11. Signal Transduction Pathways
The binding of a specific signaling molecule to a receptor in the plasma membrane triggers the first step in the signal transduction pathway.
The molecules that relay a signal from receptor to response are mostly proteins.
The original signaling molecule is not physically passed along the pathway, only the information is passed on.
At each step, the signal is transduced into a different form, usually a shape change in a protein. #1

12. Protein Phosphorylation and Dephosphorylation
In many pathways, the signal is transmitted by a cascade of protein phosphorylations.
Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation.
Cytoplasmic protein kinases phosphorylate serine or threonine.
Usually phosphorylation activates a protein.
Protein phosphatases remove the phosphates from proteins, a process called dephosphorylation.
Usually dephosphorylation inactivates a protein (when signal is no longer present).
Phosphatases also make the protein kinases available for resuse.
***This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off or up or down, as required.

13. Small Molecules and Ions as Second Messengers
The extracellular signal molecule (ligand) that binds to the receptor is a pathway’s “first messenger.”
Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion.
Second messengers participate in pathways initiated by GPCRs and RTKs.
Cyclic AMP and calcium ions are common second messengers.

14. Cyclic AMP
Cyclic AMP (cAMP) is one of the most widely used second messengers.
Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal.
An enzyme, called phosphodiesterase, converts cAMP to AMP in the absence of an extracellular signal.
Adenylyl cyclase
Phosphodiesterase
Pyrophosphate
H2O P
P i
ATP
cAMP
AMP

15. First messenger (signaling molecule such as epinephrine)
Many signal molecules trigger formation of cAMP (epinephrine is an example).
Other components of cAMP pathways are G proteins, G protein-coupled receptors, and protein kinases.
cAMP as Second Messanger
First messenger bind to GPCR.
G protein activated.
G protein activates adenylyl cyclase.
Adenylyl cyclase atalyzes the conversion of ATP to cAMP.
cAMP usually activates protein kinase A, which phosphorylates various other proteins.
Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase.
Adenylyl cyclase
G protein
G protein-coupled receptor
GTP
ATP
Second messenger
cAMP
Protein kinase A
Cellular responses

16. Calcium Ions and Inositol Triphosphate (IP3)
Calcium ions (Ca2+) act as a second messenger in many pathways.
Increase cytosolic concentration of Ca2+ causes many responses in animal cells (muscle cell contraction, secretion, and cell division).
Cells use Ca2+ as a second messenger in pathways triggered by both GPCRs and RTKs.
Calcium is an important second messenger because cells can regulate its concentration.
Under normal conditions, the concentration of Ca2+ in the cytoplasm is lower than outside the cell and in the ER.
A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol.
Pathways leading to the release of calcium involve inositol triphosphate (IP3) and diacylglycerol (DAG) as additional second messengers.

17. Signaling molecule (first messenger)
Figure
EXTRA- CELLULAR FLUID
Signaling molecule (first messenger)
G protein
DAG
GTP
G protein-coupled receptor
PIP2
Phospholipase C
IP3 (second messenger)
IP3-gated calcium channel
Figure Calcium and IP3 in signaling pathways.
Various proteins activated
Cellular responses
Endoplasmic reticulum (ER)
Ca2
Ca2 (second messenger)
CYTOSOL

18. Concept Check
What is a protein kinase, and what is its role in a signal transduction pathway?
When a signal transduction pathway involves a phosphorylation cascade, how does the cell’s response get turned off?
Upon activation of phospholipase C by the binding of a ligand to a receptor, what effect does the IP3-gated calcium channel have on Ca2+ concentration in the cytosol?