biochem chapter 13

What is the first step in signal transduction?

A stimulus or trigger releases the primary messenger.

What happens during reception of the primary messenger?

Receptors transfer information from extracellular space to intracellular environment.

What is the role of second messengers in signal transduction?

They relay information from the receptor to downstream targets and amplify the signal.

What is a possible physiological response in signal transduction?

Activation or inhibition of final effectors such as enzymes controlling metabolic pathways.

Why is termination of signaling important?

Signaling must be stopped after information has been transferred.

what are the 5 steps of the signal transduction pathway

Signal, Reception, Amplification, Transduction, and Response

What do receptor proteins do?

They bind extracellular molecules and transfer information across the membrane to the intracellular space.

What type of receptor is the β2-adrenergic receptor?

It is a 7 transmembrane-helix receptor (7TM).

What is the function of dimeric receptors?

They recruit kinases, such as the Growth hormone (GH) receptor.

What type of receptor is the epidermal growth factor receptor (EGFR)?

It is a dimeric receptor kinase.

What do receptors act on to produce second messengers?

They act on transducers.

What are some examples of transducers?

trimeric g protein, adenylate cyclase, protein kinase a, janus kinase

What role do transducers play in signaling?

They act in cascades to regulate and amplify signaling.

What is the function of Grb-2, Sos, and Ras?

They are involved in signaling as a monomeric G protein.

What kinases are associated with PIP3 signaling?

irs, pip3 kinase, pip3-dependent kinase, akt kinase

What are 7TM receptors?

Ubiquitous receptors with seven transmembrane helices that receive various signals such as hormones, odorants, neurotransmitters, and photons.

What happens upon ligand binding to a 7TM receptor?

It causes a structural change in the cytoplasmic domain.

What is an example of a 7TM receptor?

The β2 adrenergic receptor recognizes epinephrine (adrenaline).

What is the function of 7TM receptors?

They receive signals from hormones, odorants, neurotransmitters, and photons.

What is the structure of a 7TM receptor?

It has seven transmembrane helices embedded in the cell membrane.

What does the β2 adrenergic receptor respond to?

It responds to epinephrine (adrenaline).

What is the ligand specificity of 7TM receptors?

7TM receptors have different ligand specificity despite having similar structure and mechanisms.

What percentage of drugs in use target 7TM receptors?

~50% of drugs in use target 7TM receptors.

What response does the B2 adrenergic receptor activate?

'Fight or flight' response

What type of receptor is the ẞ2 adrenergic receptor?

It is a G-protein coupled receptor (GPCR).

What happens when epinephrine binds to the ẞ2 adrenergic receptor?

It causes a conformational change on the cytoplasmic side.

What is activated by the conformational change in the ẞ2 adrenergic receptor?

A G-protein Ga is activated.

What does the activated G-protein Ga exchange during activation?

It exchanges GDP for GTP.

What occurs to GTP after it is activated?

GTP spontaneously hydrolyzes to GDP + P₁.

What is the effect of one receptor on Ga subunits?

One receptor can activate many Ga subunits, leading to signal amplification.

What are 7TM receptors also known as?

They are known as G-protein coupled receptors (GPCRs).

What are the subunits of G proteins?

alpha, beta, gamma

Where does GDP/GTP binding occur in G proteins?

In the α-subunit

Inactive; Gβγ binds to Ga

What is the state of G protein when bound to GDP?

What happens to G protein when it binds GTP?

Becomes active; Ga dissociates from Gβγ

What can dissociated Gα bind to?

Adenylate cyclase

What is the role of adenylate cyclase in G protein activation?

It is activated by dissociated Gα

What does GAP stand for?

GTPase activating protein

What is the function of GAP?

Stimulates GTP hydrolysis

What inherent activity does Go have?

Enzymatic activity

What does GEF stand for?

Guanine-nucleotide exchange factor

What is the role of GEF?

Exchanges GDP for GTP

What activates GPCR?

Guanine-nucleotide exchange factor (GEF)

What is released from G protein upon GTP binding?

Ga is released.

What enzyme is activated by Ga?

Adenylate cyclase is activated.

What does adenylate cyclase produce?

Cyclic AMP (cAMP), a second messenger.

What is the effect of one active adenylate cyclase enzyme?

It can produce multiple cAMP molecules (signal amplification).

What is the role of cAMP in signal amplification?

It acts as a second messenger in the signaling pathway.

What activates Protein kinase A?

cAMP

What does cAMP do to the catalytic subunits of Protein kinase A?

Activates them by binding

What resets the GPCR pathway?

Dissociation of the ligand

What enzymatic activity does Ga have?

Hydrolyzes GTP

What happens to G proteins after GTP hydrolysis?

They become inactive

What mediates olfaction?

GPCRs (G protein-coupled receptors)

What are the three second messengers involved in the phosphoinositide cascade?

PIP2, DAG, IP3

What enzyme cleaves PIP₂ in the phosphoinositide cascade?

Phospholipase C

What does IP3 cause the release of from intracellular stores?

Ca2+ from the endoplasmic reticulum (ER)

Which two molecules activate Protein kinase C?

Ca2+ and DAG

How quickly does IP3 degrade?

Within seconds

What is produced when PIP₂ is cleaved?

DAG and IP3

What is the role of DAG in the phosphoinositide cascade?

Activates Protein kinase C

What is the role of Ca2+ in cells?

Ca2+ is a versatile intracellular messenger that regulates various cellular functions.

What protein binds almost all Ca2+ in cells?

Calmodulin

How many EF hands does calmodulin have?

4

What happens when Ca2+ stores are released?

Calmodulin is activated

What does the calmodulin-Ca2+ complex bind to?

CaM kinase.

What does CaM kinase do?

phosphorylates target proteins.

What pump is stimulated by calmodulin-Ca2+?

The Ca2+-ATPase pump

What is the effect of the Ca2+-ATPase pump?

restores intracellular Ca2+ levels.

What do dimerized receptors act as or recruit?

Kinases

What can receptor tyrosine kinases do upon ligand binding?

Phosphorylate substrates

What links receptor activation to Ras activation?

Adaptor Grb-2

What is Ras?

A small G protein (small GTPase)

What is Ras's downstream effect through a series of phosphorylations?

Cell growth

What are Small GTPases regulated similarly to?

G proteins

What is the GEF for Ras?

Sos

What activity does Ras have?

Slow GTP hydrolase activity

What helps with GTP hydrolysis in Ras?

GAP

What does the Ras subfamily regulate?

Cell growth through serine or threonine protein kinases

What type of kinase does the growth hormone (GH) receptor recruit upon activation?

Tyrosine kinase

What happens to the GH receptor upon binding of one ligand molecule?

It dimerizes

What is the state of kinases when attached to a monomeric receptor?

Inactive

Which kinase is the GH receptor associated with?

Janus kinase 2 (JAK2)

What happens to JAK2 upon dimerization?

JAK2 cross-phosphorylates.

What activates JAK2?

Phosphorylation

What does activated JAK2 phosphorylate?

STAT5.

Where does phosphorylated STAT5 go?

the nucleus.

What does STAT5 regulate in the nucleus?

gene expression.

What activates the insulin receptor?

Cross-phosphorylation upon insulin binding

What are phosphorylated by the insulin receptor tyrosine kinase?

Insulin receptor substrates (IRS)

What does IRS activate in the insulin signaling pathway?

PI3K

What does PI3K phosphorylate?

PIP₂

What does PIP₃ activate in the signaling pathway?

PDK1

What does PDK1 activate?

Akt

What increases on the cell surface due to Akt activation?

Glucose transporters (GLUT4)

What is cancer caused by?

Unregulated cell growth

How do mutations in signal transduction proteins affect tumors?

They can contribute to tumorigenesis

What does overexpression of EGFR lead to?

Increased cell division

What happens to Ras proteins when they are mutated?

They become unable to hydrolyze GTP

What are Ras proteins and EGFR classified as?

Proto-oncogenes