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BIOC2003 > Fast Hormonal Signal Transduction Processes > Flashcards

Fast Hormonal Signal Transduction Processes Flashcards

1
Q

Define ‘Signal Transduction’.

A

Signal transduction is the process whereby extracellular substances such as hormones alter the metabolism of a cell.

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2
Q

What do chemical messengers do in multicellular organisms?

A

Chemical messengers allow coordinated physiological responses to occur in different situations.

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3
Q

Discuss ‘fight or flight’ as an example of signal transduction.

A

In ‘fight or flight’, adrenaline is released by the adrenal glands. Adrenaline has the overall effect of preparing the body for sudden action, but the specific effects on different tissues are diverse.

LIVER: glycogenolysis and gluconeogenesis are stimulated, and glycolysis is inhibited.

SKELETAL MUSCLE: both glycogenolysis and glycolysis are stimulated

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4
Q

Outline the five general steps of signal transduction.

A
  1. Hormone is released. The hormone may enter into the bloodstream in order to reach targets all over the body, or may only be released into the tissue fluid, to reach nearby cells.
  2. Hormone binds to receptor on plasma membrane of cell. Hormone binding induces a conformational change in the receptors cytosolic region that alters its function.
  3. The concentration of a secondary messenger is increased through enzymatic action.
  4. The ‘effectors’ are stimulated or inhibited by the secondary messenger. These may be pumps, enzymes, or gene transcription factors, for example.
  5. The signal is shut down. It may be that the pathway becomes unresponsive to the stimulus, or that the stimulus is removed.
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5
Q

How are hormones specific in signal transduction?

A

Hormones are often released only into the local area, and therefore does not stimulate cells in the wrong location, e.g. NT

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6
Q

How are receptors specific in signal transduction?

A

Each cell expresses a specific group of receptors, so it only responds to certain hormones. Different receptors can bind the same hormone but stimulate the production of secondary messengers

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7
Q

How are secondary messengers specific in signal transduction?

A

Each secondary messenger has specific effects, the messenger involved depends on both the hormone and receptor expressed

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8
Q

How are effectors specific in signal transduction

A

Cells also express different isoforms of ‘effectors’, e.g. enzymes, so that the effect of a secondary messenger on a particular effector can differ between tissues

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9
Q

Discuss the sensitivity of hormones in signal transduction.

A

For some hormones, the conc. reaching the target cells are very low, e.g. insulin is effective at only 10^(-10) M.

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10
Q

Discuss the sensitivity of receptors in signal transduction.

A

Hormone receptors have a high affinity for their hormone. The complementarity of binding site is such that only very low concentrations are needed to stimulate the cell.

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11
Q

Discuss the sensitivity of secondary messengers in signal transduction.

A

The enzyme catalysing the formation of the secondary messenger is a point of ‘amplification’ - the binding of hormone to one receptor can stimulate the production of many molecules of secondary messenger.

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12
Q

Discuss the sensitivity of effectors in signal transduction.

A

Some effectors are stimulated, while some are inhibited. By this mechanism, enzymes favouring one pathway are activated, while the opposing pathway is shut down. In this way, the metabolism of the cell is completely turned around.

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13
Q

Outline how a signal is desensitised when the hormone is no longer present

A

The initiation of a signal often stimulates enzymes that will shut the signal down when the hormone is no longer present.

There is often an enzyme that breaks down the secondary messenger, or that acts in opposition to enzymes activated by the secondary messenger.

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14
Q

Outline how a signal is desensitised, even in the presence of a hormone.

A

Even in the presence of the hormone, desensitisation can occur - this is where the signal transduction pathway is no longer stimulated, despite the continued presence of the hormone.

Insulin sensitivity is increased after exercise (in muscle), but is decreased in type II diabetes, for reasons unknown

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15
Q

Discuss integration in signal transduction.

A
  1. Cells express multiple hormone receptors on their cell surface, and can be exposed to many different hormones simultaneously
  2. Each different receptor can bind its respective hormone at the same time as other receptors are binding their hormones
  3. Different receptors may modulate the concentrations of the same secondary messengers
  4. Different signalling pathways may alter the same effectors, fine-tuning the cell’s response
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16
Q

What are “allosteric effects”?

A

Allosteric effects are conformational changes that occur in proteins when they bind particular substances, particularly for hormones and their receptors.

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17
Q

Give some brief examples of allosteric effects.

A

RECEPTOR HORMONE
induces conformational changes in the cytosolic domain

GPCRs
causes the alpha-subunit to dissociate from the beta-gamma subunits

Ca2+ CALMODULIN
exposes hydrophobic areas that allow the calmodulin to interact with other proteins

cAMP: PKA(R)
causes the regulatory subunits to dissociate, activating the catalytic subunits

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18
Q

Do allosteric effects amplify transduction?

A

Allosteric effects do NOT allow amplification of the signal; they typically cause transduction to stay the same, or get worse.

Binding of proteins is also important for bringing into the correct location for their activity

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19
Q

Discuss the phosphorylation of target proteins are phosphorylated?

A

It induces large structural changes and is catalysed by protein kinases.

Negative charges can disrupt electrostatic interactions, and the phosphoryl group can form several H-bonds.

The phosphorylation of proteins may be inhibitory or stimulatory; some proteins have several phosphorylation sites, each of different type.

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20
Q

What are the two main classes of protein kinase (and phosphatase)?

A
  1. Serine/Threonine Kinases

2. Tyrosine Kinases

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21
Q

What are the functions of these kinases?

A

Each kinase phosphorylates residues in a particular consensus sequence, that can be found on its target proteins.

Each kinase can phosphorylate multiple target proteins, so they represent points in the signalling pathway where the signal can be AMPLIFIED.

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22
Q

What are protein domains?

A

Protein domains are the assembly of proteins into large signalling transduction complexes is based in large part on several recurring protein domains with high affinity for certain types of sequences.

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23
Q

Provide some examples of protein domains.

A

Tyr-P : PTB (Phosphotyrosine Bindong Domain)
Tyr-P : SH 2 (Src homology 2)

3 x Proline : SH3 (Src homology 3)

P-Inosital-P-P : PH (Pleckstrin homology)

Ca2+ : EF-Hand

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24
Q

How are hormones defined, and what are the three main types of hormone?

A

Hormones are defined by the distance over which the act.

  1. ENDOCRINE
    act on cells far from the site of release
  2. PARACRINE
    act on nearby cells
  3. AUTOCRINE
    act on the cell that released the hormone
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25
Q

Provide an example of each type of hormone.

A

ENDOCRINE
insulin, adrenaline

PARACRINE
found in immune responses

AUTOCRINE
T-cells, interleukin-2

26
Q

Name the four main classes of hormone receptors, also providing an example

A

LGICs
e.g. ACh receptor

RECEPTOR ENZYMES
e.g. insulin receptor

ENZYME-RECRUITING RECEPTORS
e.g. cytokine receptors

GPCRs
e.g. adrenaline receptors

27
Q

What is the function of hormone LGICs?

A

The signal is transduced to the cell via the change in membrane potential when the ion channel is opened.

28
Q

What is the function of hormone receptor enzymes?

A

Enzymatic activity of receptor is activated.

29
Q

What is the function of hormone enzyme-recruiting receptors?

A

Hormone binding induces the recruitment and activation of protein kinases.

30
Q

What is the function of hormone GPCRs?

A

Hormone binding activates GTP-binding proteins.

31
Q

What are GPCRs?

A

G-Protein Coupled Receptors are the largest class of cell-surface receptors and are the most commonly used drug targets.

They are involved in responses to hormones, neurotransmitters, odours, tastes, and light.

32
Q

What is the function of hormone-bound GPCRs?

A

Hormone-bound receptor causes the exchange of GDP for GTP, activating the G(alpha) subunit.

The dissociated G(alpha) subunit then interacts with an enzyme, until it hyddrolyses the GTP to GDP, becoming inactive again.

33
Q

What are the four groups of G(alpha) subunits?

A

G(s) - activates adenylyl cyclase, increasing [cAMP]

G(i) - inhibits adenylyl cyclase reducing [cAMP]

G(q) - activates phosphoilpase C, increasing [DAG], [IP3], [Ca2+]

G(t) - activates retinal cyclic GMP phophodiesterase

34
Q

How many isoforms exist for G(beta) and G(gamma)?

A

G(beta) - 5 isoforms

G(gamma) - 6 isoforms

35
Q

Which cytosolic loops interact with G-proteins?

A

3/4 cytosolic loop

5/6 cytosolic loop

36
Q

What are the functions of the G(beta-gamma) complexes?

A

G(beta-gamma) complexes are involved in signalling, either by cooperating in transduction, or by shutting the pathway down.

37
Q

What is the effect of the interaction of adrenaline with beta-adrenoceptors?

A

beta-adrenoceptors activate G(s)

38
Q

What kind of protein kinase is Protein Kinase A, and what is its structure?

A

Protein Kinase A is a Serine/Threonine Kinase.

It is an R2C2 heterotetramer

It recognises the consensus sequence:
Arg, Arg, X, Ser/Thr, Z

The regulatory subunits have the sequence:
Arg, Arg, Gly, Ala, Ile

39
Q

Outline the function of Protein Kinase A.

A

Protein Kinase A phosphorylates several enzymes, such as hormone-sensitive lipase (+), acetyl CoA carboxylase (-), glycogen synthase (-), and the transcription factor CREB (+).

Protein kinase A is thus able to immediately alter metabolic pathways, and have longer term effects via gene transcription.

40
Q

What are the three points of amplification?

A
  1. The adrenaline:receptor complex is able to catalyse GDP:GTP exchange on multiple G-proteins; each activated G(a) subunit can only bind to one adenylyl cyclase
  2. Each active adenylyl cyclase can catalyse the formation of many molecules of cAMP; it takes 4 molecules of cAMP to activate 2 x PKA subunits
  3. Each active PKA subunit can phosphorylate many proteins
41
Q

What are the three points of amplification for Protein Kinase A?

A
  1. The adrenaline:receptor complex is able to catalyse GDP:GTP exchange on multiple G-proteins; each activated G(a) subunit can only bind to one adenylyl cyclase
  2. Each active adenylyl cyclase can catalyse the formation of many molecules of cAMP; it takes 4 molecules of cAMP to activate 2 x PKA subunits
  3. Each active PKA subunit can phosphorylate many proteins
42
Q

What type of protein kinase is Protein Kinase C?

What is its function?

A

Protein kinase C is a Ser/Thr kinase; it is a cytosolic protein.

The increase in cytosolic [Ca++] allows PKC to interact with membrane phospholipids.

Contact with DAG activates PKC, allowing it to phosphorylate its target membrane proteins.

43
Q

What type of protein kinase is Protein Kinase C?

What is its function?

A

Protein kinase C is a Ser/Thr kinase; it is a cytosolic protein.

The increase in cytosolic [Ca++] allows PKC to interact with membrane phospholipids.

Contact with DAG activates PKC, allowing it to phosphorylate its target membrane proteins.

44
Q

What is the normal cytosolic concentration of Ca2+?

What are the functions of Ca2+?

A

Cytosolic [Ca2+] is maintained at roughly 0.1uM. Upon stimulation, it can increase almost 100-fold

Ca2+ binds to calmodulin, a ‘calcium sensor’ found in most eukaryotic cells.

Ca2+ binding induces a large conformational change in calmodulin, that allows it to bind other proteins, for example, the CaM kinases. These CaM kinases can then go on to phosphorylate their target proteins.

45
Q

What is the normal cytosolic concentration of Ca2+?

What are the functions of Ca2+?

A

Cytosolic [Ca2+] is maintained at roughly 0.1uM. Upon stimulation, it can increase almost 100-fold

Ca2+ binds to calmodulin, a ‘calcium sensor’ found in most eukaryotic cells.

Ca2+ binding induces a large conformational change in calmodulin, that allows it to bind other proteins, for example, the CaM kinases. These CaM kinases can then go on to phosphorylate their target proteins.

46
Q

What are the points of amplification for Protein Kinase C?

A
  1. The adrenaline:receptor complex is able to catalyse GDP:GTP exchange on multiple G-proteins
  2. Each phospholipase C can catalyse the formation of many molecules of IP3 and DAG
  3. Each activated Ca channel releases many calcium ions
  4. Each activated PKC can phosphorylate many membrane proteins
47
Q

What is the function of receptor tyrosine kinases (RTKs)?

A

RTKs function as dimers with an extracellular hormone-binding domain and an intracellular protein tyrosine kinase domain.

Upon binding of hormone, RTK monomers cross-phosphorylate each other.

Phosphorylation of the RTK makes it a site of attachment for proteins with SH2 domains, or PTB domains - localising proteins at the membrane.

48
Q

Describe the function of RTKs at the insulin receptor.

A

For the insulin receptor, cross-phosphorylation causes the kinase to become fully active.

49
Q

State the five-stage mechanism of Epidermal Growth Factor Receptor (EGFR).

A
  1. Binding of EGF to each EGFR monomer induces a structural change that allows the monomers to dimerize; proximity of the cytosolic domains allows cross-phosphorylation
  2. Tyrosine-phosphates act as docking sites for Grb-2, which is attached to Sos
  3. Sos catalyses the exchange of GDP for GTP on membrane-bound Ras, activating it
  4. GTP:Ras binds and activates Raf, a membrane-bound protein kinase
  5. A series of protein kinases are phosphorylated and activated, resulting in the phosphorylation of several transcription factors, altering their activity
50
Q

Discuss the structure and function of Growth factor receptor-bound protein 2 (Grb-2)

A

Grb-2 is an ‘adaptor protein’ - it only acts as a ‘bridge’ to link proteins

It is composed of an SH2 domain, sandwiched between two SH3 domains

(SH2 binds sequences containing phospha-Tyr, and
SH3binds proline-rich sequences)

51
Q

Discuss the structure and function of Growth factor receptor-bound protein 2 (Grb-2).

A

Grb-2 is an ‘adaptor protein’ - it only acts as a ‘bridge’ to link proteins

It is composed of an SH2 domain, sandwiched between two SH3 domains

(SH2 binds sequences containing phospha-Tyr, and
SH3binds proline-rich sequences)

52
Q

Discuss the structure and function of Sos.

A

Sos is a guanine nucleotide exchange factor (GEF), meaning it catalyses the exchange of GDP for GTP on the Ras protein, but only when it has been recruited to the membrane via Grb-2.

53
Q

Discuss the structure and function of Ras

A

Ras is a small G-protein. Unlike the heterotrimeric G-proteins, Ras is monomeric.

Ras also has a slower GTPase activity (0.02/min) than heterotrimeric G-proteins (3/min)

GTPase activity can be increased roughly 10^5-fold by GAPs (GTPase activating proteins)

Ras:GTP binds to, and activates, Raf.

54
Q

Outline the mechanism of Insulin Receptor Signalling.

A
  1. Insulin binding to dimeric receptor forces PTK domains together, followed by x-pho
  2. First round of x-pho fully activates kinase activity, and is followed by more x-pho
  3. These phosphorylated Tyr residues act as docking sites for IRS-1, which get phosphorylated
  4. Phosphorylated IRS-1 can bind PI-3KK which, now located at the membrane, phosphorylates PIP2 at position 3, forming PIP3
  5. PIP3 allows both PDK1 and PKB to associate with the membrane via their PH domains
  6. Phosphorylated PKB dissociates from the membrane and phosphorylates its target protein
55
Q

Discuss the structure and function of insulin receptor substrate-1 (IRS-1)

A

IRS-1 is phosphorylated on several Tyr residues

IRS-1 is already associated with the membrane due to its PH domain, which can bind PIP2. Once phosphorylated, it can dissociate from the insulin receptor.

It is a docking protein, as it can bind many proteins, including Grb-2 (thereby activing the MAPK pathway)

56
Q

What other protein can assemble at the phosphorylated insulin receptor?

A

IRS-2 (a homologous protein)

57
Q

What is the function of PDK1?

A

When PDK1 binds PIP3 via its PH domain, this localises it to the membrane and activates it.

58
Q

What is the function of protein kinase B (PKB)?

A

PKB also binds PIP3 via a PH domain, it is then phosphorylated and activated by PDK1.

PKB is responsible for phosphorylating several proteins in both the cytosol and the nucleus

59
Q

What are the amplification points of the insulin receptor?

A
  1. The insulin receptor can phosphorylate multiple IRS-1 proteins
  2. The PI-3K can catalyse the formation of multiple PIP3 molecules
  3. PDK1 catalyses the formation of multiple PKB enzymes
  4. PKB can go on to phosphorylate many proteins
60
Q

What are the amplification points of the insulin receptor?

A
  1. The insulin receptor can phosphorylate multiple IRS-1 proteins
  2. The PI-3K can catalyse the formation of multiple PIP3 molecules
  3. PDK1 catalyses the formation of multiple PKB enzymes
  4. PKB can go on to phosphorylate many proteins

BIOC2003 (8 decks)

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