Week 7: Principles of Cell Signalling

Question 1

What are the four (five) main signalling types?

Answer 1

Endocrine - distant target cells - hormones
Paracrine - close target cells - local mediator
Synaptic - neurons - neurotransmitters
Contact-Dependent - membrane bound signal molecule + receptor
Autocrine - Same cell

Question 2

What is adrenaline (epinephrine)?

Answer 2

Peptide hormone - derivative of tyrosine - adrenal gland - increases BP, HR and metabolism

Question 3

What is cortisol?

Answer 3

Steroid hormone (derivative of cholesterol) - adrenal gland - affects protein, glucose and lipid metabolism in tissues

Question 4

What is estradiol?

Answer 4

Steroid hormone (derivative of cholesterol) - ovary - induces and maintains secondary female sex characteristics.

Question 5

What is insulin?

Answer 5

Protein hormone - Beta cells of pancreas - stimulates glucose uptake, protein synth and lipid synth.

Question 6

What is testosterone?

Answer 6

Steroid hormone - testis - induces and maintains secondary male sex characteristics.

Question 7

What is thyroid hormone (thyroxine)?

Answer 7

Peptide hormone (derivative of tyrosine) - thyroid gland - simulates metabolism in many cell types

Question 8

What is Epidermal growth factors (EGF)?

Answer 8

Local mediator protein - various cells - stimulates epidermal and other cell types to proliferate

Question 9

What is platelet-derived growth factor (PDGR)?

Answer 9

Local mediator protein - stimulates cells to proliferate

Question 10

What is nerve growth factor (NGF)?

Answer 10

Local mediator protein - promotes survival of certain neurons

Question 11

What is histamine?

Answer 11

Local mediator protein found in mast cells - causes blood vessels to dilate and become leaky - causes inflammation.

Question 12

What is nitric oxide (NO)?

Answer 12

Local mediator dissolved gas - nerve cells, endothelial cells lining blood vessels - causes smooth muscle to relax and regulates nerve cell activity.

Question 13

What is acetylcholine?

Answer 13

Neurotransmitter - excitatory at many nerve-muscle synapses and in central NS.

Question 14

What is gamma- aminobutyric acid (GABA)?

Answer 14

Neurotransmitter - inhibitory in CNS

Question 15

What is Delta?

Answer 15

Contact-dependent signal molecule - transmembrane protein - prospective neurons and other cells - inhibits neighboring cells from becoming specialized in same way as signaling cell.

Question 16

Describe Dictyostelium discoideum

Answer 16

chemoattractant - cAMP causes cells to aggregate. Growth -> aggregation -> mound -> finger -> slug -> culmination -> fruiting body -> spores.

Question 17

Describe slow vs. fast signalling?

Answer 17

Fast is where signal molecule binds to cell-surface receptor protein which then directly alters protein function leading to altered cytoplasmic machinery and alters cell behaviour. Slow occurs when the receptor affects the DNA/RNA which leads to altered protein synthesis, causing altered cytoplasmic machinery and altered cell behaviour.

Question 18

What are the two main types of hormone receptors?

Answer 18

Cell-surface - which bind to receptor which affects an intracellular signalling molecule. Intracellular receptors - small hydrophobic signal molecule enters cell and binds to intracellular receptor. Examples: cortisol, estradiol, T, thyroxine

Question 19

Describe cortisol’s path (see diagram)

Answer 19

Cortisol is released by adrenal glands in stressful situations and enters the cell membrane where it binds to a nuclear receptor protein and causes conformational changes to it, activating the complex. This activated complex moves into the nucleus and binds to the regulatory region of the target gene to activate its transcription.

Question 20

Describe NO’s path

Answer 20

Acetylcholine binds to a membrane receptor which activates NO synthase (NOS). NOS turns arginine into NO which diffuses across the cell membrane. It can then bind to guanylyl cyclase in smooth muscle cells which turns GTP into cyclic GMP causing rapid relaxation of the muscle cell.

Question 21

Describe the path of an extracellular signal molecule

Answer 21

Extracellular signal molecule → receptor protein → intracellular signaling molecules → effector proteins (metabolic enzyme, cytoskeletal protein, transcription regulator) → target cell responses (altered metabolism, altered cell shape/movement, altered gene expression)

Question 22

Describe the process between parallel and compensatory paths that regulate the same process.

Answer 22

Extracellular signal binds to a receptor causing primary transduction of signal to become other signalling molecules (relay). This molecule then goes on to transduce and amplify the signal by creating small intracellular messenger molecules which integrate to cause effect which is distributed to cause altered metabolism, cell shape or movement and altered gene expression.

Question 23

Describe positive feedback

Answer 23

(X→ Y - Y has positive influence on X)

Question 24

Describe negative feedback

Answer 24

Y has negative influence on X

Question 25

Describe blood glucose homeostasis feedback loop

Answer 25

High BG → more insulin secreted. Low BG → more glucagon secreted.

Question 26

How do intracellular signaling proteins act as molecular switches

Answer 26

addition/removal of phosphate as activator/inhibitor.

Question 27

Describe signaling by protein phosphorylation

Answer 27

The signal causes a protein kinase to turn ATP -> ADP which then turns the target protein on, the signal is then transduced and protein phosphatase cleaves the phosphate is removed, the protein is deactivated.

Question 28

Describe signaling by GTP-binding proteins

Answer 28

Signal comes in causing GTP to bind to the protein, replacing GDP. The protein is now activated. The signal is transduced. GTP is hydrolyzed to form GDP and the protein is now inactive.

Question 29

Describe the control of monomeric GTPases

Answer 29

Controlled by two regulatory proteins - GEFs and GAPs. GEF causes the monomeric GTPase protein to let go of GDP and bind GTP. The monomeric GTPase is now active. GAP causes the GTP to be hydrolyzed and the monomeric GTPase is now inactive.

Question 30

What are the 3 main categories of cell surface receptors?

Answer 30

Ion-Channel Coupled receptors -signal molecule binds to receptor, allows for movement of ions across channel. G-Protein Coupled receptors - signal molecule binds to receptor - activates G protein which links and activates an enzyme Enzyme-Coupled receptors - signal molecule binds to receptor and activates - or activates and associated enzyme

Question 31

What are G Protein-coupled receptors?

Answer 31

Multi-pass transmembrane proteins - alpha, beta and gamma subunits alpha -subunit of heterotrimeric G-protein expels GDP and picks of GTP. Stimulation of GPCRs activates G-protein subunits. alpha-subunit of heterotrimeric G-protein shuts itself off by hydrolyzing bound GTP to GDP.

Question 32

Describe how G proteins regulate ion channels

Answer 32

Acetylcholine activates the alpha subunit and beta-gamma complex. The beta gamma complex interacts with potassium channels causing them to open. The alpha subunit is then phosphorylated and deactivated, causing the units to reassemble and the potassium channel to close.

Question 33

How do G proteins cause release of second messenger molecules that act on intracellular signaling proteins?

Answer 33

Many G Proteins activate membrane-bound enzymes that produce small messenger molecules

Question 34

What is the role of cAMP?

Answer 34

can activate enzymes and turn on genes - production is tightly regulated. ATP -> adenylyl cyclase and is hydrolyzed to cleave 2 phosphate groups creating cyclic AMP. Cyclic AMP phosphodiesterase hydrolyzes cAMP to form AMP.

Question 35

What are some cell responses mediated by cAMP?

Answer 35

Epinephrine -> heart -> increase HR and force of contraction. Epinephrine -> skeletal muscle -> glycogen breakdown. Epinephrine -> fat -> fat breakdown. ACTH -> adrenal gland -> cortisol secretion.

Question 36

Describe the role of cAMP and PKA in glucose homeostasis - activating enzymes

Answer 36

Epinephrine actiavtes the GPCR (adrenergic receptor) which activates the alpha subunit. The alpha subunit binds with adenylyl cyclase to activate it. It turns ATP into cAMP which interacts with inactive PKA to activate it. active pKA interacts with inactive phosphorylase kinase, causing ATP to be phosphorylated, resulting in phosphorylated active phosphorylase kinase which then interacts with inactive glycogen phosphorylase using ATP to phosphorylate it to active it leading to glycogen breakdown.

Question 37

Describe the role of cAMP and PKA in glucose homeostasis - tuning on genes

Answer 37

Inactive PKA binds with cAMP which is now activated and enters the nucleus where it activates a transcription regulator via phosphorylation allowing it to transcribe the target gene.

Question 38

Describe how the Inositol phospholipid pathway triggers a rise in intracellular Ca2+

Answer 38

The signal molecule activates GPCR which activates the beta gamma subunit which activates phospholipase C which acts on inositol phospholipid to seperate IP3 and diacylglycerol. Diacylglycerol joins with PKC. The IP3 opens a calcium channel in the ER causing CA2+ to bind to PKC along with diacylglycerol creating an activated PKC.

Question 39

What are some cell responses mediated by phospholipase C?

Answer 39

Vasopressin -> liver -> glycogen breakdown Acetylcholine -> pancrease -> secretion of amylase Acetylcholine -> smooth muscle -> contraction Thrombin -> blood platelets -> aggregate

Question 40

Describe the autophosphorylation of RTK

Answer 40

A signal molecule in the form of a dimer binds with two RTKs causing them to become active. They then begin to autophosphorylate causing different signaling proteins to bind and become activated /

Question 41

What can most RTKs do?

Answer 41

Most RTK (receptor tyrosine kinase) activate monomeric GTPase Ras. They do this by phosphorylating an adaptor protein bound to Ras-GEF which then activates an inactive Ras protein by switching its GDP for GTP. This activates it and transmits the signal.

Question 42

Describe how Ras activates a MAP-kinase signaling molecule

Answer 42

The actiavted Ras can activate MAP kinase kinase kinase which hydrolyses ATP for ADP activating MAP kinase kinase which then hydrolyzes another ATP to activate MAP kinase which phosphorylates a final ATP which then phosphorylates other proteins and transcription regulators to change protein activity and gene expression.

Question 43

What can Ras mutations cause?

Answer 43

Cancer

Question 44

Describe how RTKs activate PI3-kinase to produce lipid docking sites in plasma membrane

Answer 44

A survival signal dimer activates RTK which phosphorylates PI 3-kinase to activate it. This then phosphorylates inositol phospholipid which then binds with protein kinase 1 where it interacts with Akt along with protein kinase 2 fto relay the signal by activated Akt (which is protein kinase B)

Question 45

What does activated Akt do? What does Bad do? How do they interact?

Answer 45

Activated Akt promotes cell survival. Bad promotes apoptosis by binding to and inhibiting Bcl2 - Akt phosphorylates Bad inactivating it. Bad is bound to inactive Bcl2. Active Akt phosphorylates the Bad causing it to be inactivated but releasing active Bcl2 which promotes cell survival by inhibiting apoptosis.

Question 46

Describe Tor activation by Akt

Answer 46

Stimulates cell growth. Growth factor binds to RTK which activates PI 3-kinase, which activates Akt which activates Tor which causes inhibition of protein degradation and stimulation of protein synthesis - cell growth.

Question 47

What does the integration of the protein kinase network achieve?

Answer 47

Integration of information to control complex cell behaviours.