8/15/17

Question 1

Signal transduction

Answer 1

The processing of extra cellular signals to effect a change in the internal workings of a cell

Question 2

3 Major classes of second messengers

Answer 2

Cyclic nucleotides: cAMP, cGMP

Inositol triphosphate and diacylglycerol

Ca2+ ions

Question 3

Why different cells respond differently to the same signal

Answer 3

Difference in receptor structure

Difference in internal signaling pathway

Question 4

Cholinergic neuron

Answer 4

Release acetylcholine that binds to acetylcholine receptors on skeletal muscle cells

Question 5

Myasthenia Gravis

Answer 5

Autoimmune disease that causes muscle weakness and fatigue

Autoantibodies bind to ACh receptors, block signaling, receptors internalized and degraded

Treat by using acetylcholinesterase inhibitors, slow ACh breakdown to raise ACh conc. to compensate for the lower amount of receptors

Question 6

Speed of extracellular signal effects

Answer 6

Immediate cell modification: like change in cell shape/activity, caused by changes in protein activity like phosphorylation

Long term changes:
Ike change in growth rate or differentiation, changes in gene expression and protein synthesis

Question 7

G Protein-Coupled Receptors

Answer 7

Extra cellular ligand binding domain

Transmembrane domain that crosses plasma membrane 7 times

Intracellular domain that binds G-protein

G-proteins are enzymes that are active when bound to GTP, inactive when bound to GDP

Question 8

Activation of G-proteins

Answer 8

Ligand binding to the receptor causes conformational changes that allow the alpha subunit of the G-protein to exchange GDP for GTP

The alpha (still bound to GTP) and beta/gamma subunit dissociate from the complex to move on and activate OR inhibit a target protein

Question 9

G-protein structure

Answer 9

Hydrophilic but alpha and gamma subunits are lipid linked to the cell membrane

Beta subunit is bound only to the gamma subunit

Question 10

Enzyme-linked receptors

Answer 10

Produce long term effects on the cell like cell growth, differentiation, proliferation, or survival

Signal molecules called growth factors

Question 11

Tyrosine kinases

Answer 11

Single-pass reads,embrace protein with an extracellular receptor and an intracellular tyrosine kinase domain

Typically dimerized by ligand binding

Binding of growth factor has conformational change that activates cross phosphorylation

SH2 domain containing proteins bind to the phisphorylated Tyrs, some are only for structure and are called adaptors, others are REGULATORY molecules like kinases or GTP-binding proteins

Question 12

Ion channel receptors

Answer 12

Transduction of neural signals

Neurotransmitters bind and open/close ion channel

Question 13

Intracellular receptors

Answer 13

Small, hydrophobic molecules travel in extracellular fluid attached to a carrier protein

Dissociate from carrier protein to diffuse across plasma membrane

Captured by intracellular receptor and shuttled to nucleus where they affect gene expression

Steroid hormones, thyroid hormones, and retinoids

Question 14

Gases as signaling molecules

Answer 14

ACh binds to an endothelial cell receptor and activates Nitric Oxide Synthase that makes NO from arginine

NO diffuses across plasma membrane to neighboring cells and binds to Guanylate Cyclase to produce cGMP

Increased cGMP results in relaxation of smooth muscle cells

Question 15

Vasodilation

Answer 15

NO has localized (paracrine) effects

NO causes the smooth muscle cells within blood vessels to relax, creates vasodilation

Nitroglycerin broken down to NO, treats angina or inadequate blood flow to the heart

Question 16

NO and cGMP on blood pressure

Answer 16

Vasodilation results in lower blood pressure

fatal if combine with other drugs that activate this pathway like those for pulmonary hypertension

Pulmonary hypertension: narrowing of lung vasculature with increased blood pressure, creates shortness of breath and swelling of hands/feet

Viagra is a cGMP phosphodiesterase inhibitor

Question 17

cAMP production and degradation

Answer 17

Adenylate cyclase, regulated by the G-protein alpha subunit (Gs stimulates and Gi inhibits)

cAMP phosphodiesterase, is constantly active

Question 18

cAMP Pathway

Answer 18

Stimulation of adenylyl cyclase produces cAMP

cAMP activates protein kinase A (PKA)

PKA phosphorylates proteins in cytosol or go to nucleus to activate proteins for gene transcription

Question 19

Clinical examples of cAMP

Answer 19

1. Epinephrine and norepinephrine bind to adrenergic receptors (G-protein coupled receptor)

Increased heart rate, block receptors to treat hypertension (beta blockers are agonists of adrenergic receptors)

2. Cholera toxin ADP-ribosylates the alpha subunit of Gs proteins so can’t hydrolyze GTP to GDP and stay always active

High cAMP causes flow of water into intestinal lumen, killer diarrhea

Question 20

PI and Ca2+ signaling

Answer 20

Alpha subunit of a G protein activates phospholipase C

Breaks PIP2 into IP3 and diacylglycerol

IP3 opens ion channel of ER lumen, Ca2+ rises in the cytosol

Diacylglycerol activates (along with Ca2+) Protein Kinase C, which phosphorylates other proteins into activation

Question 21

Ras

Answer 21

GTP binding protein downstream of receptor tyrosine kinases, activated by almost all RTK

Activates the MAP kinase pathway, are activated by cell stress so help with cell survival

Ras-activating protein binds to adaptor protein of RTK and then switches GDP on Ras protein for a GTP

Active Ras protein activates MAP-K-K-K, which phosphorylates MAP-K-K, which gets MAP-K to phosphorylates other proteins and gene regulatory proteins

Cause changes in protein activity and changes in gene expression

Question 22

Ras clinical

Answer 22

Mutations in Ras present in 30% of all cancers

Mutant Ras genes are one type of oncogenes

Question 23

PI-3 Kinase Pathway

Answer 23

Ras and other signaling molecules activate PI-3 kinase which phosphorylates phosphatidylinositol

Phosphorylated inositol stay attached to the membrane to activate other signaling molecules

Stimulate cell growth and survival

Question 24

JAK-STAT pathway

Answer 24

Cytokine receptor that have associated cytoplasmic kinases associated with it (JAK) to do Tyr kinase activity, cytokine binding leads to cross phosphorylation of the receptor

STAT gene regulatory proteins bind to the phosphorylated cytokine receptor and are activated

Activated STATs dimerize to travel to the nucleus to affect gene expression

Important for immunity and inflammation

Question 25

Examples of JAK-STAT signaling

Answer 25

Gamma-interferon: activates macrophage

Alpha-interferon: up cell resistance to viral infection

Erythropoietin: stimulates erythrocyte production

JAK inhibitors for inflammatory diseases like rheumatoid arthritis and psoriasis

Question 26

TGF-Beta pathway

Answer 26

Play a role in development (Transforming growth factor)

TGF-Beta binds to the receptor and the receptor phosphorylates itself through a Ser/Thr domain

Activated receptor binds SMAD and phosphorylates it

Activated SMAD dissociates from the receptor and binds to a different SMAD

Travel to the nucleus and affect gene expression

Question 27

G-protein linked receptors in heart function

Answer 27

Beta-adrenergic receptor regulate contractile the of heart muscle, bind epi and norepinephrine

Activated alpha subunit activates adenylyl cyclase and PKA

PKA phosphorylates cytoplasmic targets that regulate contractility, relaxation, and heart rate

A G-protein receptor kinase (GRK2) phosphorylates overactive beta adrenergic receptors, Beta-arrestin binds

Question 28

G-protein linked receptors desensitization

Answer 28

Chronic stress, certain disease states make high levels of epi and norepinephrine, prevents continual receptor activation

Downregulation: decrease receptor synthesis or increase degradation (slow mechanism)

Sequestration: internalization of receptor (rapid mechanism)

Inactivation: phosphorylation of the receptor so the G-protein can’t associate (rapid mechanism)

Question 29

G-protein linked receptor inactivation

Answer 29

G-protein linked receptor kinase phosphorylates an activated receptor

Arrestin binds to the phosphorylated receptor, the receptor is desensitized

Question 30

Insulin receptor signaling

Answer 30

Insulin receptor is pre-dimerized with Cys residues linking alpha and beta subunits, is a Tyr kinase receptor

Insulin binding activates MAP kinase and PI-3K pathways

MAP kinase: Elliot growth and proliferation

PI-3K: cell survival and proliferation, make macromolecules, cause GLUT-4 to be inserted into the plasma membrane

Question 31

PI-3K pathway in insulin signaling

Answer 31

PI-3K converts PIP2 to PIP3 to activate a kinase called AKT

AKt has downstream effects like increased glucose metabolism

PTEN (a phosphatase) inactivates this pathway

PI-3K signaling important in cancer