OSU PHYSIO 6101 - Lecture 3 Cell Signaling

Comprehensive review of Lecture

Why is cell-to-cell communication critically important in a multicellular organism?

It is critically important for appropriate and integrated physiological responses to changes in the internal and/or external environment.

What mediates cell-to-cell communication?

Chemical messengers and their receptors.

What are the 4 broad categories of chemical messengers that make possible cell-to-cell communication?

Neurotransmitters; hormones; paracrine agents; autocrine agents.

How do the 4 broad categories of chemical messengers differ?

They differ in the distance they travel.

What is a receptor?

A specialized area of the cell membrane that are sensitive to chemicals and when activated they cause the cell to change its behavior.

T/F Most receptors are transmembrane proteins

True

What do nuclear intracellular receptors mainly recognize?

Lipid-soluble messengers (e.g. steroids).

What are the four major factors that impact receptor recognition and activation?

Specificity, affinity, saturation, and competition.

What is specificty?

The binding site of a receptor has a specific shape that only fits specific messengers.

What is affinity?

The force of binding between messenger and receptor.

What is saturation?

The degree to which the receptors on a cell are fully occupied by a messenger.

What is competition?

Different molecules with similar structure compete for the same binding site.

What is an agonist?

A chemical messenger that binds to a receptor and triggers the normal response. It is used to describe a drug that mimics the action of the normal messenger.

Pseudoephedrine mimics the action of epinephrine. What type of agent is it?

It is an agonist.

What is an antagonist?

A molecule that binds to a receptor and but does not elicit a response. They can be called “blockers”.

β-blockers mimic the action of epinephrine and norepinephrine but do not trigger the action caused by the normal messenger. What type of agent is it?

It is an antagonist.

Is the number of receptors in the cell membrane constant?

No. The number of receptors in the cell membrane is dynamic and can change in response to a stimulus over time.

When is the number of receptors down regulated?

When there is a high extracellular concentration of a messenger for some time, the total number of receptors for that messenger will decrease. This results in desensitization.

When is the number of receptors up regulated?

When there is a low extracellular concentration of a messenger for some time, the total number of receptors for that messenger will increase. This results in increased sensitivity.

What are the 6 steps of the signal transduction pathway?

Receptor recognition, receptor activation, signal transduction, signal modulation, cell response, and termination.

What happens during signal transduction?

The extracellular signal, via the activated receptor, is converted (i.e., transduced) into an intracellular message.

What is the end result of transduction?

The production of a second messenger that triggers a cascade of events which leads to a change in the activity of effector molecules.

How can changes in effector activity often occur?

Intracellular kinases or intracellular phosphatases

What do intracellular kinases do in signal transduction?

They add phosphate groups to either intermediates of the cascade or to the final effector molecules.

What do intracellular phosphatases do in signal transduction?

They remove phosphate groups.

What are some examples of cell responses that can occur?

Changes in membrane permeability or electrical state; cell metabolism; secretory activity; proliferation/differentiation; contractile activity; and other changes.

How can a single messenger molecule orchestrate an integrated, whole-body response?

The molecule binds to receptors on multiple cell types but each cell may have a cell-specific response.

What example is given for an integrated response?

Response to stress when epinephrine acts as the primary messenger.

What must signaling cascades have?

Controls that terminate the response. Termination can occur anytime during the cascade.

What is an example of signal termination?

Decreasing the concentration of the chemical messenger or downregulation of the receptor.

What are the two classes of primary messengers?

Lipid-soluble primary messengers and water-soluble primary messengers.

What are lipid-soluble primary messengers also called?

Genomic messengers.

Where are receptors for lipid-soluble primary messengers mostly located?

Intracellularly: in the cytosol or nucleus.

What do lipid-soluble primary messengers alter?

Rates of gene transcription and protein synthesis.

Can water-soluble primary messengers pass through lipid bilayers?

No. They cannot pass through lipid bilayers because they are lipid insoluble/ hydrophilic.

Where are receptors for water-soluble primary messengers located?

They are plasma membrane proteins.

What are the 4 types of water-soluble primary messenger mechanisms?

1. Receptors that function as ion channels (i.e., ligand-gated ion channels); 2. Receptors that function as enzymes; 3. Receptors that interact with cytoplasmic enzymes; 4. Receptors that interact with G-proteins.

What happens during activation of ligand-gated ion channels?

The first messenger binds with the receptor which opens the ion channel and causes the cell response.

What happens when the primary messenger binds to a receptor that function as enzymes?

The binding of the primary messenger causes receptor’s autophosphorylation which allows the receptor to then interact with the intracellular second messenger.

What happens when the primary messenger binds to receptors that interact with cytoplasmic enzymes?

Activated receptor binds to intracellular Janus Kinases (JAK). JAKs then phosphorylate intracellular proteins in the second messenger cascade.

What are examples of cell responses to binding of receptors which interact with cytoplasmic enzymes?

Response to cytokines and increased protein synthesis are listed as examples.

What is the largest category of receptors?

G-protein couples receptors. There are around 800 types identified right now.

What does heterotrimeric mean for G proteins on the slide?

G proteins are heterotrimeric, contain 3 subunits (α, β and γ), and are bound to the inner leaflet of the membrane.

What does the α subunit of a G protein do with GTP?

The α subunit both binds and hydrolyzes guanosine triphosphate (GTP).

What do the β and γ subunits do?

The β and γ subunits anchor the protein in the membrane.

What can the α subunit do to effector proteins?

The α subunit can interact with and activate effector proteins.

What is the first step of the 6-step sequence for G protein regulation?

In the inactive state, GDP (guanosine diphosphate) is bound to the α subunit of a G protein and the inactive G protein is bound to a receptor.

What is the second step of G protein regulation?

When a primary messenger binds to a G-protein coupled receptor, the receptor undergoes a conformational change that increases the affinity of the G protein’s α subunit for GTP (guanosine triphosphate).

What is the third step of G protein regulation?

GTP replaces GDP on the α subunit and the α subunit splits from the β-γ complex.

What is the fourth step of G protein regulation?

The separated α subunit interacts with and activates another membrane bound protein, the effector (usually an ion channel or an enzyme), and they begin the effector cascade.

What is the fifth step of G protein regulation?

The α subunit hydrolyzes GTP to GDP + inorganic phosphate (Pi) and returns inactive.

What is the sixth step of G protein regulation?

The inactive α subunit associates back to the β-γ complex, the G protein binds once more to the receptor, and the system is reset for activation.

If the effector protein of a G-protein coupled receptor is an ion channel, what can happen?

The G-protein may cause the channel to open or close.

If the effector protein of a G-protein coupled receptor is an enzyme, what can happen?

A second messenger is produced which serves as a relay from the plasma membrane to the biochemical machinery inside the cell.

What happens in Step 1 of the cAMP signal pathway?

The primary messenger binds to the receptor, causing the receptor to undergo a conformational change and activate the G protein.

What happens in Step 2 of the cAMP signal pathway?

Once activated the Gs activates its target, the enzyme adenylyl cyclase.

What happens in Step 3 of the cAMP signal pathway?

Activated adenylyl cyclase catalyzes the conversion of ATP to cyclic AMP (cAMP).

What happens in Step 4 of the cAMP signal pathway?

Inside the cell, cAMP activates cAMP-dependent protein kinases (such as PKA).

What happens in Step 5 of the cAMP signal pathway?

cAMP-dependent kinases (i.e. PKA) phosphorylate and activate target effectors that induce a cell’s response.

What happens in Step 6 of the cAMP signal pathway?

cAMP is converted to linear AMP by phosphodiesterases to terminate signaling.

What is the 6-step sequence for cAMP signaling transduction (slide 35, MEMORIZE!)?

1. Ligand binding to a receptor causes G protein activation; 2. α subunit of G protein activates adenylyl cyclase; 3. Adenylyl cyclase converts ATP to cAMP; 4. cAMP activates a cAMP-dependent kinase (usually PKA); 5. Activated PKA phosphorylates intracellular proteins to induce cell’s response; 6. Termination of the signaling cascade is caused by phosphodiesterases that convert cAMP to linear AMP OR by protein phosphatases that dephosphorylate proteins.

What are the two mechanisms listed for termination of the cAMP signaling cascade?

Phosphodiesterases convert cAMP to linear AMP OR protein phosphatases dephosphorylate proteins.

What does activated cAMP-dependent protein kinase (e.g., PKA) phosphorylate?

Intracellular proteins and plasma membrane ion channels.

What does indirect G protein gating of ion channels utilize?

A second messenger pathway.

What does activation of adenylyl cyclase initiate?

An “amplification cascade” of events.

Which second messenger enters the cell through plasma membrane ion channels or is released from the endoplasmic reticulum?

Ca2+.

What is the source of Ca2+ as a second messenger according to the table?

Enters cell through plasma membrane ion channels or is released from endoplasmic reticulum.