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Molecular Cell Biology FoM > Signal Transduction and Second Messengers > Flashcards

Signal Transduction and Second Messengers Flashcards

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1
Q

Define autocrine

A

The cell producing the messenger expresses receptors on its surface that can respond to that messenger

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2
Q

Define paracrine

A

Messenger molecules travel short distances through the extracellular space to cells in close proximity to the cell generating the message (often unstable/easily degraded), e.g. acetlycholine

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3
Q

Define endocrine

A

Messenger molecules reach target cells via the blood stream (aka hormones), e.g. steroid hormones

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4
Q

How can cells communicate?

A
  • Chemical messengers
  • Directo contact
  • Electrically
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5
Q

What are signalling molecules?

A

Molecules of the right shape dock using non covalent bonds to their receptors with great specificity
Primary signal molecules/first messengers/receptor ligands

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6
Q

What can signalling molecules be classified as?

A
  • Neurotransmitters
  • Hormones
  • Growth factors and cytokines
  • Vitamin A and D derivatives
  • Nitric oxide
  • Regardless of classification, all binds cellular receptors and elicit a response
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7
Q

What are neurotransmitters?

A
  • Small amino acids (5-35) or their derivatives
  • Released by neurons at synaptic junctions in response to electrical stimulus (action potential)
  • Quickly degraded and small to prepare neuron for next impulse
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8
Q

Give two examples of neurotransmitters and their actions

A
  • Acetylcholine at neuromuscular junction- botulinum toxin prevents release
  • GABA- primary inhibitory neurotransmitter in brain, anti-stress/anti-anxiety effects, important in aiding control of all convulsive disorders like epilepsy
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9
Q

What are eicosanoids?

A
  • Derived from arachidonic acid in plasma membrane
  • Contains 4 double bonds
  • Common fatty acid in phospholipids
  • Makes local hormones
  • Involved in all aspects of inflammation- blocking leukotriene receptors can play a role in management of inflammatory diseases
  • Anti-Inflame drugs act by cyclooxyrgenase and therefore prostanoid synthesis
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10
Q

What is arachidonic acid?

A

20-carbon polyunsaturated fatty acid ‘Eicosa’

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11
Q

What must a cell have in order to respond to an extracellular chemical signal?

A
  • Cell must express receptors that specifically recognise and bind to a particular messenger molecule
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12
Q

What two ways can a signal molecule bind?

A
  • Via plasma membrane, polar
  • Via intracellular receptors (cytosolic receptors), most are gene-specific transcription factors, steroid hormones (e.g. cortisol, oestrogen), thyroid hormones, vitamins A and D
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13
Q

Give examples of classical steroid ligands

A
  • Sex steroid (e.g. oestrogen)
  • Glucocorticoid (e.g. cortisol)
  • Mineralocorticoid (e.g. aldosterone)
  • Vitamins A and D
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14
Q

Why are signalling molecules able to easily cross membranes?

A

They are hydrophobic

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15
Q

Where can receptors be located?

A
  • Cytoplasm (e.g. cortisol)

- Or nucleus (e.g. oestrogen)

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16
Q

What happens when signalling molecules bind to a receptor?

A

Steroid hormone-receptor complex receptors bind to the hormone response element (HRE) of the gene, activating promoter and initiating gene transcription

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17
Q

What is GTPase?

A

Large family of hydrolase enzymes that bind to nucleotide guanosine triphosphate (GTP) and hydrolyse it to guanosine diphosphate (GDP)- cleavage of high energy bond

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18
Q

What is phosphodiesterase (PDE)?

A

Enzyme that breaks the phosphodiester bond

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19
Q

What is the cyclic nucleotide phosphodiesterase group?

A

Group of enzymes that degrade bond in 2nd messenger molecules cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate)

20
Q

What is kinase?

A

Catalyse transfer of phosphate group from donor, such ATP, to an acceptor (i.e. switch on)
Kinase kinase and kinase kinase kinases activate kinases

21
Q

What are phosphatases?

A

An enzyme that catalyses the hydrolysis of organic phosphates in a specific (acid or alkaline) environment

22
Q

Describe nitric oxide as a messenger

A
  • Formed from amino acid arginine and oxygen by NO synthase

- Acts as a second messenger in smooth muscle relaxation pathway and as a primary signal molecule

23
Q

How does nitric oxide act?

A
  • Locally by diffusing through cell membrane (lipophilic)
  • Binding and activating an intracellular receptor (guanylyl cyclase) which converts GTP to second messenger cGMP
  • cGMP activates kinase that phosphorylates target proteins to elicit smooth muscle relaxation- vasodilation
24
Q

What is phosphodiesterase 5 (PDE5)?

A

An intracellular that degrades cGMP

25
Q

What occurs when PDE5 is inhibited?

A

Permits the cyclic nucleotide (cGMP) to remain active as a second messenger, leading to physiological outcome

26
Q

What are plasma membrane receptors?

A
  • Extracellular domain (binds to chemical messenger with high affinity)
  • Membrane spanning domain (alpha helices)
  • Intercellular domain (initiates signal transduction)
27
Q

What are the major effects produced by plasma membrane receptors?

A
  • Rapid and immediate effects on cellular ion levels or activation/inhibition of enzymes
  • Slower changes in rate of gene expression for a specific set of proteins
  • Often signal transduction pathways can diverge to produce both effects
28
Q

What are the major classes of plasma membrane receptors?

A
  • Ion channel receptors (e.g. acetylcholine)
  • G-protein coupled receptors (or heptahelical receptors)
  • Receptors tyrosine kinases
29
Q

Describe the structure of G-protein coupled receptors

A
  • 7 alpha helices that span the membrane, domains and binds a G protein (GTP activity)
  • G proteins are heterotrimers, they have alpha beta and gamma subunits
30
Q

What are the features of G-protein coupled receptor?

A
  • Extracellular binding domain is specific
  • No kinase/enzymatic activity, signal is transducer through G protein (accessory protein)
  • Stimulatory (GS) or inhibitory (GI)
31
Q

Describe the action of G protein coupled receptors

A
  • Primary signalling molecule binds to its specific receptor
  • Upon ligand binding (active), associated G protein exchanges GDP for GTP
  • Time for hydrolysis depends on length of signal
  • Activated G protein stimulates effector molecule, e.g. adenylyl cyclase
32
Q

What occurs with second messengers with G protein coupled receptors?

A
  • Second messengers, e.g. cAMP created, binds to further downstream proteins (i.e. kinase A activated by cAMP)
  • Requires energy
  • Inactive state, G protein had GDP associated with it
  • Alpha unit that can be stimulatory/inhibitory
33
Q

Describe cAMP as a second messenger

A
  • Activated by adenylyl cyclase (AC) and converts ATP to cAMP
  • Transfers signals of hormones such as glucagon and adrenalin
  • Where 1st messenger can bind to single receptor, cAMP can stimulate many activities
  • Elicit cellular response via PKA into 2 ways
34
Q

In what ways does cAMP elicit a cellular response via protein kinase A?

A
  • Phosphorylates a large number of metabolic downstream enzymes in the cytosol
  • Alters gene transcription in the nucleus
35
Q

How is signal amplification achieved?

A
  • G proteins use a chain of other messengers to amplify relayed signal
  • One receptor-ligand complex can activate many G proteins
  • Each G protein can activate many adenylyl cyclases
  • Each adenylyl cyclase does ATP-> cAMP
  • cAMP activates protein kinases that activate several molecules of target enzyme
36
Q

How is signal amplification switched off?

A
  • Enzyme degradation of cAMP by phosphodiesterases
37
Q

How do G proteins activate phospholipase C?

A
  • GTP bound G protein activates effectors other then adenylyl cyclase, e.g. phospholipase C (releases IP3)
  • IP3 diffuses through cytosol to ER and binds to receptor opening a channel for calcium ions
  • DAG and calcium activate protein kinase C, cascades signal through series of phosphorylation reactions
  • DAG, IP3 and calcium ions are all second messengers
38
Q

What is phospholipase C?

A

An enzyme that degrades cell membrane phosphatidyl inositol (PTI) releasing inositol triphosphate (IP3) and leaving diacyl glycerol (DAG)

39
Q

Describe adrenaline-receptor action

A
  • One ligand

- Multiple effects

40
Q

What is the link between G proteins and disease?

A
  • Sometimes G protein receptor is defective- e.g. GPCR rhodopsin causes retinitis pigments
  • Sometimes associated G protein is effective
41
Q

What are receptor tyrosine kinases?

A
  • Exist as inactive monomers
  • Activated by growth and differentiation factors (e.g. EGF) or by metabolic regulators like insulin
  • Tyrosine residues on the intracellular domain
42
Q

Describe the action of receptor tyrosine kinases

A
  • Primary signalling molecule ligand binds to TKRs, causing them to dimerise
  • This activates tyrosine kinase portion of protein when kinase domain switched on, autophosphorylation occurs at residues
  • Able to activate adaptor proteins- RAS G protein
  • RAS activates MAPKKK (Raf)- autophosphorylation
  • MAPKKK activates MAPKK (MEKK)
  • Activated MAPK (ERK)
    Activated relay proteins can then pass on signal within cell to elicit. a response
43
Q

What do all kinase reactions require?

A

ATP

44
Q

What is Trastuzumab (Herceptin)

A
  • Herceptin monoclonal antibody targets HER2 tyrosine kinase receptor found on 25% of breast cancer cells
  • Binding of Herceptin to HER2 blocks binding of natural ligand, epidermal growth factor (EGF) to HER2 and subsequent downstream signalling cell to grow and proliferate
  • Target this to prevent
45
Q

What do uncontrolled signalling pathways lead to?

A

Cancer

46
Q

Describe uncontrolled signalling pathways

A
  • BCR_ABL fusion gene
  • Translocation in which long arm of chrome. 22 attaches to long arm of chrome. 9
  • Acquired mutation
  • Contains TK domain, transmits a cell proliferation signal, constitutively switched on
  • BCR-ABL (inappropriately fused) oncogene instructs constant cell division, prevents apoptosis for leukaemia
  • Causes chronic myelegnous leukaemia
47
Q

What is Imatnib (Gleevec)?

A

Successful anti-cancer drug, binds to TK domain and deactivated erroneous signal

Molecular Cell Biology FoM (12 decks)

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