Cell Signaling Flashcards
Chemical messengers (ligands) bind to
specific target-cell proteins known as receptors
Water-soluble ligands
bind to receptors located at the plasma membrane E.g.: (Glucagon, Prolactin)
Water-soluble ligands diffuse through extracellular (interstitial) fluid.
Can’t typically get through the cell membrane
Bind to transmembrane receptors. Bind to portion of receptor outside the cell. Causes conformational change to portion of receptor inside the cell.
Lipid-soluble ligands
bind to an intracellular receptor E.g.:
(Thyroid hormone)
Lipid-soluble ligands diffuse through the cell membrane.
Why?
Bind to a receptor in the cytosol or nucleus
Bind DNA
Change transcription of genes
Receptor Specificity
Lock-and-key fit
Receptor = lock
Ligand = key
Specificity is higher when fit is better
Target cells contain receptors for
the ligand of interest
Binding leads to response
Affinity
Affinity: The strength with which a ligand binds to its receptor
High ligand-receptor affinity= binds quickly and more bound
Competition
Competitors (e.g., drugs)= compete for receptors, reduce amount of binding
Pathways Initiated by Lipid-Soluble Messengers
Bind to a receptor in the cytosol or nucleus
Can up-regulate or down-regulate
gene transcription.
Takes time to see cell response
Usually, 20+ minutes
Slow, but sustained response
Pathways Initiated by Water-Soluble Messengers
Bind to transmembrane receptors
Receptors activate downstream mediators
Can affect DNA transcription
Also have many other effects in the cell
Faster response but Less sustained
Receptors that are Ligand-Gated Ion Channels
Ligand binding= conformational change= opens ion channel
Ion specific
* Usually 1-2 ion types
* Limited by size and charge
Ions diffuse across membrane
* Net direction determined by
concentration gradient and charge of ion
Can change membrane potential of a cell
* Ex. Serotonin Receptors
Ligand: Serotonin (5-HT)
Ion Permeability: Na⁺, K⁺, and Ca²⁺.
Receptors that Function as Enzymes
Most are Tyrosine Kinases
Binding changes the conformation of the receptor= enzymatic portion is activated
Active kinase= phosphorylates proteins using ATP= cell’s response
One Exception: Cyclic GMP
Guanylyl cyclase: functions as both a receptor and as an enzyme
Receptors that Interact with Cytoplasmic Janus Kinases
have cytoplasmic kinases, called Janus kinases (JAKs) associated
with the receptor
Ligand binding cause receptor
conformational change= activates JAK
Active JAK= phosphorylates proteins= cell’s response
G Protein-Coupled Receptors
- Ligand binding
- Receptor conformational change
- G Protein Activation by Increasing
affinity of the alpha subunit for GTP - Alpha subunit dissociates from the beta and gamma subunits
- Links up with either an ion channel or an enzyme
- Leads to change in membrane potential or second messenger cascade, respectively
Major Second Messengers
A- Adenylyl cyclase (enzyme) and cyclic AMP (2nd messenger)
B- Phospholipase C (enzyme), Diacylglycerol (DAG), Inositol
Triphosphate (IP3)(both are 2nd messengers)
C- Calcium-calmodulin
A- Cyclic AMP Second Messenger System
- Ligand binding activates G-protein coupled receptor (Gs) S. stimulatory
- Alpha subunit binds GTP and activates adenylyl cyclase
- Activated adenylyl cyclase converts ATP to cAMP
- cAMP activates cAMP-dependent protein kinase A (PKA) which . . .
- phosphorylates proteins= cell’s response
The second messenger cascade ends
when cAMP phosphodiesterase breaks down cAMP to AMP.
Second Messenger Signal Amplification
First messengers (ligands)
* Made and released in very small amounts
* Can produce large cellular responses through signal amplification
Second messengers
* Many more are produced
* Each phosphorylates many target enzymes
* Each enzyme phosphorylates many final products
A variety of cellular responses from cAMP
Activated cAMP-dependent protein kinase can phosphorylate many different proteins
- Activates some
- Inhibits others
- Can turn on one pathway while turning off another
E.g. Epinephrine inhibits glycogen synthesis at the same time it stimulates glycogen break down
B- The Second Messenger Pathway
G protein is called, activated by binding a first messenger
Activated then activates phospholipase C (PLC)
PLC catalyzes the breakdown of phosphatidylinositol bisphosphate ) inositol trisphosphate + (DAG) diacylglycerol
DAG activates protein
kinase C which…..
* phosphorylates proteins
cell’s response
binds to ligand-gated
channels on the ER
* They open when bound to
increased cytosolic
concentration leading to
the cell’s response
* can activate some forms of
protein kinase C, enhancing
effects of DAG
Which cellular location(s) have receptors that bind intercellular chemical messengers?
The plasma membrane, the cytosol and the nucleus
The first step in the action of any intercellular chemical messenger is the binding of the messenger to specific target-cell proteins called
receptors or receptor proteins
The ability of a foreign molecule to interfere with a natural ligand by binding to its receptor is referred to as
competition
A drug that blocks the action of a chemical messenger is referred to as a(n)
antagonist
Antihistamines are drugs that ______.
block the actions of histamine during allergic responses
If all receptors are occupied, the receptors are said to be fully
saturated
A decrease in the total number of target-cell receptors for a given messenger is referred to as receptor
down-regulation
What part of a cell do water-soluble messengers bind to?
Extracellular portion of plasma membrane protein receptors
What type of messenger includes most polypeptide hormones, neurotransmitters, and paracrine and autocrine compounds?
Water-soluble
Janus kinases are located on ______.
the cytoplasmic region of certain plasma membrane receptors
Which subunit of a G protein splits GTP into GDP and Pi, making the subunit inactive and allowing it to recombine with the other G protein subunits?
Alpha
What are the four kinds of pathways initiated by water-soluble messengers?
1- Ligand-Gated Ion Channels
2- Receptors that Function as Enzymes
3- Receptors that Interact with Cytoplasmic Janus Kinases
4- G-protein coupled receptors
What are three examples of major second messengers?
A- Adenylyl cyclase (enzyme) and cyclic AMP (2nd messenger)
B- Phospholipase C (enzyme), Diacylglycerol (DAG), Inositol
Triphosphate (IP3)(both are 2nd messengers)
C- Calcium-calmodulin
Calcium-Calmodulin, and the Calmodulin-Dependent Protein Kinase System
On binding with calcium, calmodulin
changes shape
Calcium-calmodulin activates or inhibits a large variety of enzymes and other proteins= cell’s response
Many are protein kinases
Other Messengers - Eicosanoids
Eicosanoids are a family of molecules produced from arachidonic acid (Fatty acid)
They are generated in many kinds of cells in response to different types of extracellular signals
Stimulus binds to its receptor and activates phospholipase 𝐀𝟐 (PLA𝟐)
PLA𝟐 splits off arachidonic acid from the membrane phospholipids
Arachidonic acid
* cyclooxygenase (COX) pathway= cyclic endoperoxides, prostaglandins, and thromboxanes
* lipoxygenase pathway= leukotrienes
Other Messengers - Eicosanoids
Cessation of Activity in Signal Transduction Pathways
The signal ends when
First messenger:
* metabolized by enzymes
* taken up by cells and destroyed
* diffuses away
Second messenger’s
Intracellular concentration decreases due to breakdown enzymes
–>Prevents chronic overstimulation
Receptors can be inactivated in at least three other ways:
1- Receptor becomes chemically altered (usually by
phosphorylation)= decreases its affinity for first messenger= messenger is released
2- Phosphorylation of the receptor prevents further G-protein
binding to the receptor
3- Plasma membrane receptors removed by endocytosis
Interactions of Signal Transduction Pathways
- Pathways may be active simultaneously in a single cell, undergoing complex interactions
- A single first messenger may trigger changes in the activity of more than one pathway
- Many different first messengers may simultaneously influence a cell
- “Cross talk” can occur at one or more levels among the various signal
transduction pathways
