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BIOC2003 > Fast Hormonal Signal Transduction Processes > Flashcards

Fast Hormonal Signal Transduction Processes Flashcards

1
Q

What is signal transduction ?

A

The process whereby extracellular substances such as hormones alter the metabolism of a cell.

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2
Q

What is the effect of AD (released by adrenal glands) on the body ?

A

Preparing the body for action ==> “fight or flight” response:

  • liver : glycogenesis + gluconeogenesis stimulated, inhibition of glycolysis
  • sk muscle : glycogenolysis + glycolysis stimulated
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3
Q

How do cells manage to shut down signals (after the signal has been initiated) ?

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 2nd messenger, or that acts in opposition to enzymes activated by the 2nd messenger.

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4
Q

What is receptor desensitization ?

A

This is when, even in the presence of a hormone, the signal transduction pathway is no longer stimulated (despite the continued presence of the hormone).

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5
Q

How does insulin sensitivity change after exercise ? - in type II diabetes ?

A

After exercise –> insulin sensitivity increased in muscle

Type II diabetes –> insulin sensitivity decreased

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6
Q

What are allosteric effects ?

A

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

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7
Q

Where are allosteric effects observed ?

A
  • Receptor:hormone –> induces a conformational change in the cytosolic domain
  • GPCRs:G-proteins –> causes the alpha subunit to dissociate from the beta-gamma subunits
  • Ca2+:Calmodulin –> exposes hydrophobic areas that allow the calmodulin to interact w/ other protein
  • cAMP:PKA(R) –> causes the regulatory subunits to dissociate, activating catalytic subunits
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8
Q

How do allosteric effects allow amplification of the signal?

A

They do not !

They are 1:1 ratio (or worse)

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9
Q

Why is binding of proteins important ?

A

For bringing proteins into the correct location for their activity.

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10
Q

What is phosphorylation ? -how does it work ?

A

Phosphorylation = a biochemical process catalyzed by kinases (and reverse by phosphotases) where phosphate groups are removed from ATP/GTP and added on to proteins (or other macromolecules).

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11
Q

What are the effects of phosphorylation ?

A

Phosphorylation can induce large structural changes :

  • the -ve charges can disrupt electrostatic interactions
  • the phosphoryl group can form several H bonds
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12
Q

Is phosphorylation stimulatory of inhibitory ?

A

It can be either, and some proteins can have several phosphorylation sites, some which inhibit the protein, some which stimulate it, or even some which change the protien’s function.

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13
Q

What are the two main classes of protein kinases (and thus of phosphotases) ?
What is the diffrerence between the 2 ?

A

Serine/threonine kinases –> often involve changes in level of activity (+ or -)
Tyrosine kinases –> often involve changes in binding affinity

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14
Q

How do kinases “know” which AAs to phosphorylate ?

A

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

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15
Q

Why can kinases help amplify a signal ?

A

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

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16
Q

What is the assembly of proteins into large signalling complexes based on ?
Give examples.

A

In large part on several re-occurring protein domains w/ high affinity over certain types of sequences :

  • PTB (Phosphotyrosine Binding Domain) and SH2 (Src homolgy 2) domain will both bind phosphorylated tyrosine residues
  • SH3 domains will binds proline residues
  • PH (Pleckstrin homology) domain will bind phopsho-inositol
  • EF-Hand domain (like that in calmodulin) will readily bind Ca2+ ions)
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17
Q

What are the three classes of hormones (based on the distance over which they act) ?

A

Endocrine : act on cells far from site of release, e.g. insulin and AD
Paracrine : act on nearby cells, e.g. in immune response
Autocrine : act on the cell that released the hormone, e.g.g T-cells and interleukins-2

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18
Q

What chemicals are hormones ?

A

None in particular, hormone are chemically diverse :

  • polypeptides, e.g. insulin
  • AA derivatives, e.g.AD, thryroxine
  • eicosanoids, e.g. PGs, leukotrienes
  • purines, e.g. adenosine
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19
Q

what is the general structure of a membrane receptor ?

A

Extracellular binding site, membrane spanning domain + cytosolic domain altered by hormone binding

20
Q

Name 4 types of membrane receptors (w/ examples for each).

A
  • LGICs, e.g. nAChR –> the signal is transduced to the cell via the change in MP etc. when the channel is opened
  • Receptor enzymes, e.g. insulin receptor –> enzymatic activity of receptor in activated by hormone-binding
  • Enzyme-recruiting receptors, e.g. cytokines receptors –> hormone binding induces the recruitment and activation of protein kinases
  • GPCRs, e.g. AD receptors –> hormone-binding activates GTP-binding proteins
21
Q

What are the characteristics of GPCRs ?

A
  • largest class of cell-surface receptors (several thousands known)
  • widely used as drug targets
  • involved in responses to hormones, NTs, odours, tastes and light
22
Q

How do GPCRs work ?

A
  • The hormone-bound receptor causes the exchange of GDP for GTP, activating the G-alpha subunit
  • The (dissociated) G-alpha subunit then interacts w/ an enzyme, until it hydrolyses the GTP to GDP, becoming inactive again (takes seconds to minutes)
23
Q

W/ which part of the GPCR does the G-alpha interact w/ ?

A

The 3/4 and 5/6 cytosolic interact w/ G-proteins.

24
Q

How any isoforms of the the G-alpha exist ?

How many types of G-alpha subunits exits ?

A

~ isoforms, divided into 4 groups :

  • Gs –> activates AC, increases [cAMP]
  • Gi –> inhibits AC, reducing [cAMP]
  • Gq –> activates PLC, increases [DAG], [IP3] and [Ca2+]
  • Gt –> activates retinal cGMP PDEs
25
Q

How many isoforms of G-beta and G-gamma subunits exist ?
What regulates these subunits ?
What is their role ?

A
  • 5 G-beta and 6 G-gamma
  • tissues regulate their expression of these subunits
  • the G-betta/gamma complexes may also be involved in signalling, either by cooperating in transduction, or shutting the pathway down
26
Q

How does the the beta-AR work ?

A
  • AD binds the beta-AR
  • the G-protein interacts w/ the GPCR and GDP is exchanged for GTP on the G-alpha subunit
  • G-alpha (bound to GTP) will activate AC
  • AC will convert ATP to cAMP
  • cAMP will active PKA
  • PKA is made of 2 R subunits and 2 C subunits –> cAMP work by binding the R subunits in a 2:1 ratio (2 cAMP for one R) to release the catalytic subunits
  • the C subunits can then go on to phosphorylate target proteins
27
Q

What is PKA ?

How does it work ?

A
  • a R2C2 heterotetramer, a serine/threonine kinase
  • recognizes the consensus seqence : Arg-Arg-X-Ser/Thr,Z (Z = Glu or Gln)
  • the regulatory subunits have the sequence : Arg-Arg-Gly-Ala-Ile
  • the binding of 4 cAMP to the 2 R subunits causes them to dissociate from the catalytic subunits, activating them
  • PKA phosphorylates several enzymes, such as hormone-sensitive lipase (+), acetyl CoA carboxylase (-), glycogen synthase (-), and the TF CREB (+)
  • PKA is thus able to immediately alter metabolic pathways, and have long term effects via gene transcription
28
Q

What are the points of amplification in beta-adrenergic signalling ?

A
  1. The AD:beta-AR complex is able to catalyze GDP:GTP exchange on multiple G-proteins
  2. Each active AC can catalyze the formation of many molecules of cAMP (it takes 4 molecules of cAMP to activate 2 PKA subunits)
  3. Each active PKA subunit can phosphorylate many proteins
29
Q

How is beta-adrenergic signalling shut down ?

A
  1. AD is displaced from the receptor
  2. cAMP is converted AMP by a cyclic nt PDE
  3. G-alpha(GTP) is hydrolyzed back to G-alpha(GDP)
  4. Phosphorylated proteins are de-phosphorylated by phosphotases
30
Q

How does beta-adrenergic desensitization occur ?

A
  • beta-ARK (beta-AR Kinase) phosphorylates serine and threonine residues on beta-AR
  • this will facilitate beta-arrestin binding of the beta-AR, making it unable to interact w/ G-alpha
  • this also leads to sequestration of the receptor
31
Q

How does the alpha-1-AR work ?

A
  • AD binds the receptor
  • Gq-alpha interacts w/ the receptor, GDP is exchanged for GTP
  • Gq activates PLC-beta, which hydrolyses the membrane phospholipid PIP2 (Phosphatidylinositol 4,5-bisphosphate) into IP3 (Inositol 1,4,5-triphosphate) and DAG (Diacylglycerol)
  • IP3 activates Ca2+ channels on the ER to trigger Ca2+ release into the cytosol
  • Ca2+ interacts w/ proteins and PKC, creating a binding site for DAG, recruiting PKC to the membrane
  • DAG activates PKC
32
Q

What is PKC ?

How does it work ?

A
  • a serine/threonine kinase
  • cytosolic protein
  • the icnrease in cytosolic [Ca2+] allows PKC to interact w/ membrane phospholipids
  • contact w/ DAG activates PKC, allowing it to phosphorylate its target membrane proteins
33
Q

What is the basal [Ca2+] in the cytosol ?

What about upon stimulation ?

A

The cytosolic [Ca2+] is maintained at ~0.1uM

Upon stimulation, it can increase ~100-fold

34
Q

Why effects can a rise in cytosolic [Ca2+] have on the cell ?

A
  • Ca2+ binds to calmodulin (CaM), a “Ca2+” sensor found in most eukaryotic cells
  • Ca2+ binding induces a large conformational change in CaM that allows it to bind other proteins, e.g. CaM kinases
  • these CaM kinases can then go on to phosphorylate their target proteins
  • calmodulin is also a domain in some protein, such as phosphorylase kinase (involved in glycogenolysis)
35
Q

What are the point of amplification in alpha-1-AR signalling ?

A
  1. The AD:receptor complex is able to catalyse GDP:GTP exchange on multiple G-proteins
  2. Each PLC can catalyse the formation of many molecules of IP3 and DAG
  3. Each activated Ca2+ channel releases many Ca2+ ions
  4. Each activated PKC can phosphorylate many membrane proteins
36
Q

How is alpha-1-AR signalling shut down ?

A
  • DAG –> broken down or metabolized to a different phospholipid
  • IP3 is dephosphorylated by phosphotases (3 P groups removed) back to inositol
  • Ca2+ in either pumper back in the ER by a Ca2+ ATPase or exchanged against Na+ by the NCX (antiporter)
37
Q

What are receptors serine/threonine kinases (RTKs) ?
How do they work ?
Give an example.

A
  • RTKs function as dimers, w/ an extracellular hormone-binding domain, and an intracellular protein TK domain
  • upon binding of hormone, RTK monomers cross-phosphorylate each other
  • phosphorylation of the RTK make it a site of attachment (docking site) for proteins w/ SH2 or PTB domains - localizing proteins at the membrane
  • for the insulin receptor, cross-phosphorylation causes the kinase to become fully active
38
Q

How does EGF (Epidermal Growth Factor) signalling work ?

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 (PTB domains) 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 f protein kinases are phopshrylated and activated, resulting in the phosphorylation of several TFs, altering their activity.
39
Q

What is 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 2 SH3 domains
  • the SH2 domain binds sequences containing Pohspho-Tyr
  • the SH3 domains binds Pro-rich sequences (which are present on Sos)
40
Q

What are Sos and Ras ?

How can Ras activity be increased ?

A
  • Sos = a GEF –> 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
  • Ras = a small G-protein (monomeric!)
  • Ras also has slower GTPase activity (0.02min-1 Vs ~ 3min-1) than heterotrimeric G-proteins
  • The GTPase activity can be increased ~10e5-fold by GAPs
  • Ras:GTP binds to, and activates, Raf
41
Q

How does insulin signalling work ?

A
  1. Binding of insulin to the dimeric forces the PTK domains together, followed by cross-phosphorylation.
  2. The 1st round of cross-phosphorylation fully activates the kinase, and is followed by more cross-phosphorylation.
  3. These phosphorylated Tyr residues act as docking sites for IRS-1 (Insulin Receptor Substrate 1), which gets phosphorylated.
  4. P-IRS-1 can bind PI-3K (phosphoinositide-3 kinase), which, now, located at the membrane, phosphorylated PIP2 at position 3, forming PIP3 (phosphatidylinositol-3,4,5 trisphosphate)
  5. PIP3 allows both PDK1 (phosphoinositide-dependant kinase 1) and PKB to associate w/ the membrane via their PH (pleckstrin homology) domains.
  6. Phosphorylated PKB dissociates from the membrane and phosphorylated its target proteins.
42
Q

How does IRS-1 work ?

A
  • IRS-1 = Insulin Receptor Susbstrate-1
  • IRS-1 is phosphorylated on several Tyr residues.
  • IRS-1 is already associated w/ the membrane due to its PH domain, which can bind PIP2. Once phosphorylated, it can dissociated from the insulin receptor.
  • IRS-1 is a docking protein, as it can bind many proteins, including Brb-2 (thereby activating the MAPK pathway).
  • There are other proteins that can assemble at the phophorylated insulin receptor, including IRS-2, a homologuous proteins.
  • Insulin is therefore capable of simultaneously stimulating numerous pathways, involving short-term and long-term effects
43
Q

How do PDK1 and PKB work ?

A
  • When PDK1 binds PIP3 via its PH this localizes it to the membrane and activates it
  • PKB also binds PIP3 via . PH doamin, it is then phosphorylated and activated by PDK1.
  • PKB is responsible for phosphorylating several proteins in both the cytosol and the nucleus.
44
Q

What are the amplification points in insulin signalling ?

A
  1. The insulin receptor can phosphrylate multiple ISR-1 proteins.
  2. The PI-3K can catalyse the formation of multiple PIP3 molecules.
  3. PDK1 can phosphorylate multiple PBK enzymes.
  4. PKB can go on to phosphorylated many proteins.
45
Q

How is the insulin signal shut down ?

A
  • The de-phosphorylation of phosphorylated proteins requires specific phosphotases.
  • Lipid phosphotases dephosphorylate PIP3.
  • Many of these are recruited by the active insulin receptor.
46
Q

By what other hormone(s) are the effects of insulin regulated ?
How ?

A

The effects of insulin are modulated by interactions w/ other hormones, especially glucagon.
Insulin activate PP1 (protein phosphotase 1), which counteracts the actions of PKA (stimulated by glucagon and AD).
PKA inhibits PP1 by activating an inhibitor of PP1 called inhibitor 1.

BIOC2003 (15 decks)

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