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MABS Biochemistry > lecture 16 and 17 v2 > Flashcards

lecture 16 and 17 v2 Flashcards

cellular signaling I & II

1
Q

what is a hormone?

A

a substance that is produced in one tissue or organ that is released into the blood and carried to another tissue or organ where it acts to produce a specific response.

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2
Q

what are examples of the effects of hormones?

A

Protein activation, production of second messengers, changes in transcriptional activities, etc.

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3
Q

what are examples of hormones?

A

amino acids and/or their derivatives, peptides, glycoproteins, cholesterol derivatives, fat-derived molecules.

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4
Q

what is the difference in the way hormones act intracellularly and extracellularly?

A

the external chemical signals are received by receptors on the outside face of plasma membrane and the receptors produce chemical signals on the inside of the cells which is propagated through the cell where they elicit specific cellular responses whereas chemical signals enter the cell directly and bind to an intracellular receptor having a direct effect on cell processes like DNA

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5
Q

what kind of cellular response does insulin ellicit?

A

extracellular response for signal transduction

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6
Q

if a hormone ellicit an intracellular response, it can freely diffuse across the membrane to reach its appropriate intracellular receptor, T/F?

A

F, channel receptors are used to help ferry the hormone across the membrane and this type of response illicit a DNA response

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7
Q

what are the two major classes of receptor?

A

extracellular and intracellular

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8
Q

define extracellular receptor

A

typically bind peptide/protein hormones and tyrosine derived catecholamines

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9
Q

what are some examples of what the extracellular receptors bind?

A

peptide and protein hormones
e.g., insulin, growth hormone, parathyroid hormone

tyrosine-derived catecholamines e.g., dopamine, norepinephrine, epinephrine

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10
Q

what is an intracellular receptor?

A

typically bind steroid hormones (glucocorticoids like cortisol, mineralocorticoids (like aldosterone), androgens and estrogens, and Vitamin D), retinoic acid derivatives and thyroid hormones.

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11
Q

how do extracellular receptors act?

A

Almost always act to stimulate a signal cascade, whereby proteins are activated, second messengers are produced, and many cellular proteins are affected.

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12
Q

how do intracellular receptors act?

A

Almost always act at the DNA level, altering transcription of genes (i.e., turn on or turn off expression of a given protein, etc.)

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13
Q

what are the basic steps in signaling?

A

1) recognition
2) transduction
3) transmission
4) modulation
5) response
6) termination

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14
Q

define each of the steps in cellular signaling?

A

Recognition of the hormone signal : hormone binds to specific receptor

Transduction of the signal across the membrane : Receptor conformational change

Transmission to intracellular components : Receptor activates adaptor proteins

Modulation of the effector : 2nd messengers produced, target proteins activated

Response of the cell to the signal : cell status changes

Termination of the signal : degrade second messenger, turn off target proteins

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15
Q

what are the three types of signaling?

A

endocrine, paracrine, autocrine

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16
Q

what is endocrine signaling?

A

source of hormone and target of hormone far apart, like insulin/glucagon

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17
Q

what is paracrine signaling?

A

source of hormone and target of hormone adjacent, like nerve signaling

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18
Q

what is autocrine signaling?

A

cell produces and receives its own signals, like platelet cells.

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19
Q

ID the five fundamental classes of receptors? the three general functions?

A
  • Ligand-gated ion channels
  • G-protein coupled receptors
  • Catalytic receptors – insulin receptor
  • Intracellular (steroid) receptors
  • Transmembrane proteins that release transcription factors
  • Ion channel receptors
  • Receptors that are kinases or bind kinases
  • Heptihelical (7-membrane spanning helices) receptors
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20
Q

what are the signal transduction membrane receptors? name four of them

A

G-protein linked receptors - glucagon, epinephrine, alpha and beta receptors
autophosphorylation receptor - insulin
calcium signaling - IP3 signaling
ion channel

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21
Q

name an example of a ligand gated ion channel?

A

the acetylcholine receptor

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22
Q

how does the example of the acetylcholine receptor work?

A

the acetylcholine receptor works by by having the Ach bind to the Ach receptor, which Ach is released by an electrical stimulus and so when this binds to its receptor this stimulates a conformational change in the receptor allowing K+ and Na+ ions to flow changing the membrane polarization causing a voltage change initiating an action potential

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23
Q

what kind of channels are AchR?

A

ion channels

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24
Q

how is the Ach signal terminated?

A

by acetylcholinesterase in the synaptic cleft

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25
Q

so we know that acetylcholinesterase is active when the flux of acetylcholine floods the synaptic cleft and starts degrading the Ach, what happens to the affinity of the Ach to the receptor?

A

the affinity starts to go down and this closes the Ach receptor preventing sodium from coming in and shitting down the action potential

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26
Q

of the classes of receptors we studied what is the glucagon receptor?

A

heptihelical G-protein coupled receptors

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27
Q

what are other examples of the heptihelical G-protein coupled receptor?

A

the alpha- and beta-adrenergic receptor

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28
Q

what does glucagon signal?

A

the fasting state and so it tells the cells to turn on pathways that convert energy stores to usable fuels (muscle and liver glycogen, liver) and turn off pathways that build up energy stores

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29
Q

how do the heptihelical G-protein coupled receptors work?

A

it activates adenylate cyclase to produce cAMP which activates protein kinase A which in turn phosphorylates specific target enzymes of fuel mobilization pathways. These enzymes get turned on and so activity increases whereas phosphorylated fuel storage enzymes get turned off, inactivated and after a period of time the signal is quenched by the degradation of cAMP

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30
Q

after a period of time, the signal is quenched by the degradation of cAMP, T/F?

A

True

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31
Q

T/F, as long as the cAMP is present the protein kinase A is active?

A

True

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32
Q

what are other examples of heptihelical G-protein coupled receptors?

A

cardiac myocytes, hepatocytes, many cells containing glucagon receptors.

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33
Q

since we know that cardiac myocytes and hepatocytes are g-protein coupled receptors how much further can we classify them?

A

cardiac myocytes are beta adrenergic receptors and hepatocytes are alpha adrenergic receptors

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34
Q

what are beta adrenergic receptors?

A

sympathetic stimulation of cardiac function, increases heart rate and contractility. Also can signal the “fight or flight” response.

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35
Q

what are alpha adrenergic receptors?

A

during fight or flight response, changes glucose metabolisms pathways to ensure maximum energy is available for cells.

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36
Q

what is significant about the glucagon receptor?

A

signals the fasting state…liberate stored energy from reserves to meet energy needs of cells.

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37
Q

what triggers the liver function?

A

hormonal signaling

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38
Q

how does glucagon stimulated signal transduction work?

A

signal is initiated that tells the body to release glucagon and is received by the appropriate signal and because they are g-coupled, g-protein is present and becomes activated. GDP is exchanged and GTP will go on changing the conformation of the g-protein, since this is where the exchange takes place, and no more affinity for receptor and wants to bind to adenylate cyclase (high affinity) - which is an allosteric down regulated enzyme and so now this protein protein interaction causes an upregulation of its activities, which includes the binding of ATP to produce cAMP

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39
Q

what is significant about the structure of protein kinase A?

A

its a protein tetramer, 2 regulatory and 2 catalytic. The regulatory pieces cause the catalytic pieces to be locked down tight and so when we have cAMP, it binds to regulatory subunit and it changes their conformation and catalytic subunits are let go because affinity is different and become active to phosphorylate target protein, example of allosteric activation.

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40
Q

what is the effect of the protein kinase A on the GTP?

A

g-protein is stimulated to hydrolyze the GTP into GDP and so G-protein lets go and this shuts down adenylate cyclase and cAMP is no longer made. cAMP is degraded by phosphodiesterase reducing its levels to AMP and so regulatory subunits become active and protein kinase becomes inactive. As long as glucagon signal is in blood binding and signaling continue

41
Q

name the signaling cascades that amplify the hormone signals?

A

1) One hormone binds to one receptor
2) One receptor activates one G-protein
3) One α-subunit activates one adenylate cyclase
4) One adenylate cyclase produces lots of cAMP
5) cAMP diffuses in the cell and activates lots of PKA
6) PKA phosphorylates lots of target proteins

42
Q

how does the initiation of signaling work for g-protein coupled receptors?

A
  • G-protein catalytic subunit (α) is inactive when GDP is bound
  • Hormone binding to receptor induces conformational change in receptor that is communicated physically to α subunit
  • Stimulates exchange of GDP for GTP, which activates the α subunit and causes it to release the βγ complex, which activates them.
43
Q

what is important to note in the production of second messengers for g-protein coupled receptors?

A

one hormone activates one receptor, which activates on G alpha subunit, which activates one adenylate cyclase. Adenylate cyclase then catalyzes ATP to cAMP at a high rate, producing a large amount of cAMP quickly. This cAMP will diffuse throughout the cytoplasm, where it binds to PKA, causing the transition from inactive to active PKA

44
Q

what is the effect when adenylate cyclase is activated?

A

this in turn deactivates the G alpha subunit, which dissociates from adenylate cyclase, which causes adenylate cyclase to become inactive again. So the production of cAMP stops. End result – a short lived burst of cAMP production.

45
Q

because we know there are 4 cAMP binding sites, 2 regulatory binding sites, why is this significant?

A

allows for a graded response, a little bit of glucagon sets off a small response and partial filling of the four sites and tiny bit of active protein kinase A; depends on the concentration of glucagon

46
Q

how does cAMP signal termination work?

A
  • cAMP phosphdiesterase breaks the cyclic bond to produce AMP, which does not have signaling properties.
  • Thus, the balance between AC and cAMP phosphodiesterase controls the strength and duration of the signal.
47
Q

what terminates the cAMP signal?

A
  • Phosphodiesterase breaks down cAMP
  • Decreased cAMP levels cause PKA R subunit to rebind to C subunit, inactivating it
  • No additional phosphorylation takes place
  • Phosphatases remove the phosphates from target proteins
48
Q

how is glycogen degradation in the skeletal muscle stimulated by the Gs protein coupled receptor?

A

epinephrine binds to the beta receptor and signals the need for increased muscle performance and so the cell responds by stimulating glucose production from glycogen and the cascade goes like this:

g-protein to AC to cAMP to PKA activated then downstream targets like glycogen phosphorylase to degrade glycogen, when cAMP levels fall then the PKA becomes inactive again and protein phosphorylation stops

usually protein phosphatase works to undo what PKA does and phosphodiesterase breaks down cAMP to simple AMP to stop signaling

49
Q

what happens when glycogen synthase is phosphorylated?

A

it turns off, while the glycogen phosphorylase is on

50
Q

what happens when glycogen phosphorylase is phosphorylated?

A

it turns on

51
Q

what happens when insulin is turned on?

A

insulin needs glycogen synthesis and so its going to activate glycogen phosphatase which dephosphorylates glycogen synthase and glycogen phosphorylase

52
Q

what is the effect of cAMP on gene expression?

A

cAMP response element (CRE), a type of a DNA, that recognizes a protein that has something to do with cAMP and in this case, cAMP response element binding protein which binds with cAMP binding protein (CBP) and gene transcription is initiated; any protein responsible for fasting metabolism will be activated via glucagon: proteins that break down fat in the adipose, glucose in the liver, protein that mobilize amino acids in the tissue. Same concept for insulin which affects nucleus by binding with its protein responsible for glycogen synthesis, cholesterol synthesis, fatty acid synthesis

53
Q

what is Gs?

A

Activates adenyl cyclase, increases cAMP (second messenger), also activates Ca2+ channels.

54
Q

what is Gi?

A

Inhibits adenyl cyclase, prevents cAMP production, also activates K+ channels

55
Q

what is G0?

A

Inhibits Ca2+ channels…depresses nerve activity.

56
Q

what is Gq?

A

Activates phospholipase C, which produces IP3 and increases cell Ca2+ , and produces DAG, which activates PKC…smooth muscle contraction

57
Q

what is G12/13

A

cytoskeletal remodeling, smooth muscle contraction

58
Q

*what is the alpha subunit of the g-protein?

A

also known as the Gs, the catalytic subunit, and can also be written as G alpha s

59
Q

what are three cytoplasmic protein targets of G-protein signaling pathways?

A

adenylate cyclase
phosphodiesterase
phospholipase C
phospholipase D

note the specificity of cell, receptor, and g-protein is responsible for each specific effect

60
Q

what is significant about PLC interacting wit alpha q?

A

PLC-beta becomes activated and cleaves PIP2 to become IP3(second messenger) and DAG and IP3 signals the release of Ca2+ form the ER by binding to a calcium release channel called the IP3 receptor. The IP3 then gets degraded and the channel closes

61
Q

so we also mentioned DAG (diacylglycerol), what does it do?

A

it binds PKC (protein kinase C) which attacks its target protein

62
Q

what is PLC?

A

break bond between glycerol backbone and the phosphate head group, ie.- phosphatidylcholine to phosphocholine and DAG

63
Q

what is PLD?

A

can convert PC to choline and phosphatidic acid

64
Q

what is the significance of calcium ATP transporter?

A

binds calcium and puts it back in the ER and is an active transporter because the ER has more concentration in it and cell has less concentration and ultimately this decreases the cellular calcium level, remember it is an active transporter

65
Q

what are second messengers?

A

Molecules or ions produced (or released) inside the cell in response to hormone binding to the extracellular receptor that carry the “message” to internal cellular components.

66
Q

what are some examples of second messengers?

A

1) cAMP
2) IP3
3) Ca2+
4) DAG

67
Q

how are receptors composed?

A

<p>two subunits, initially physically separated; can be heterodimers or homodimers</p>

68
Q

what stimulates the association of the two subunits of the receptor?

A

hormone binding, and so this activates the receptor resulting in phosphorylation of the receptor

69
Q

how can are the receptors phosphorylated?

A

can be done through autophosphorylation like a tyrosine kinase receptor or it can be phosphorylated by a kinase that binds like a jak-stat receptor

70
Q

what is significant about the phosphorylation sites?

A

they become docking sites aka binding sites for adaptor proteins

71
Q

what is the effect of adaptor protein binding to the phosphorylated receptor?

A

it results in activation of the adaptor protein which leave the receptor and bind cellular targets to change cellular state

72
Q

what are the three of examples of kinase/autocatalytic receptors?

A

tyrosine kinase receptors, JAK-STAT receptors, serine-threonine receptors

73
Q

how do kinase receptors work?

A

hormone comes along and binds one-half receptor and this creates high affinity for the other half and when the two pieces come together they are brought together by the hormone and so the receptor is activated by conformational changes, and they start to develop many phosphorylation sites recognized by adaptor proteins

74
Q

what is the tyrosine (remember side chain as benzene ring and -OH, great place for phosphate attachment) kinase receptor?

A

kinase receptor those tyrosine residues become phosphorylated

75
Q

what is the JAK-STAT receptor?

A

kinase receptor with associated tyrosine kinase, the receptor itself is not the kinase, but its JAK kinase turns on by signal binding, conformational change occurs and phosphorylation of the receptor occurs by its JAK kinase

76
Q

what is significant about these signal transducer proteins?

A

they are all different - different signaling pathways and they do different things in the cell, it serves as the driving force for cell growth and development and is very carefully regulated as a signaling mechanism. In some forms of cancer, the regulation of this signaling event is lost, allowing constant signaling and unrestrained cell growth.

77
Q

what are the signal transducers for the kinase receptors we named?

A

tyrosine kinase receptor - SH2 domainJAK-STAT receptor - STATSerine threonine receptor - SMAD

78
Q

how do kinase receptors work?

A

When the hormone binds, this activates the receptor to dimerize, phosphorylate itself (or become phosphorylated), which allows the adaptor proteins to bind or become active, which then activate their targets, and so on throughout the cell.

79
Q

once the protein kinase receptor is active, how does it affect the rest of the cell?

A

phosphorylation occurs and the Grb2 protein and communicates with SOS protein stating its time for SOS to let go of g-protein, the SOS protein is attached to the RAS which has GDP and this is exchanged for GTP enacting conformation change developing RAS affinity for anther protein, the RAF protein. Remember that the associated GTP becomes hydrolyzed to GDP

80
Q

what happens if nothing is holding the Ras in the GDP state?

A

it will continue to bind GTP and hydrolyze. This is highly regulated. In some forms of cancer, the regulation of this signaling event is lost, allowing constant signaling and unrestrained cell growth.

81
Q

how is the insulin receptor structured?

A

The insulin receptor is a pre-formed dimer, and each half has an α and β subunit; so the insulin receptor’s two separate domains are always together and bind insulin readily

82
Q

what is the effect of insulin binding?

A

it simulates the receptor which autophosphorylates

83
Q

what happens when the receptor is phosphorylated?

A

the phosphorylated receptor binds the insulin receptor substrate and IRS gets phosphorylated by the receptor

84
Q

what does the IRS target?

A

target proteins like Grb2, phospholipase C-γ and phosphatidyl inositol 3-kinase and so these activated target proteins affect cell processes

85
Q

Why is IP3 important?

A

it serves as the secondary messenger after the activation of PLC-γ is activated, which releases calcium as the cellular response and this is based on the insulin response, which stats its times to grow in addition to PI3 kinase

86
Q

as part of the insulin receptor mediated response, what is the action of PI3 kinase?

A

phosphorylates head group with one more phosphate activated by IRS, so PI3 kinase creates a 3 phosphate system affecting glucose metabolism

87
Q

what is transactivation?

A

something happening somewhere and then go across something for activation to happen and so we can tie intracellular receptors to transactivation by events happening in the cytoplasm causing PKA to go into nucleus and cause necessary effects

88
Q

what are DNA segments called? What is the steroid response element also known as?

A

response elements; cAMP response element

89
Q

what are the molecules that bind to intracellular receptors? Name the intracellular hormones

A

cortisol, aldosterone, thyroid hormone (T3), Vitamin D3, Retinoids(all trans retinoid acid) and 9-cis retinoic acid

90
Q

out line the steps for hormone gene regulation?

A

After the hormone enters cell (via diffusion(not simple) or carrier mediated) it binds to receptor causing dimerizationHeat shock proteins (HSP90) bound to receptor and keeps it locked down until hormone is presentso now since receptor is activated, it has a nuclear localization and binds to specific place on DNA called hormone response element and activate cis-linked genes. Note that two receptors (dimerization) were needed to bind together for complete activation because it is a graded response

91
Q

what are the shapes of the steroid.thyroid receptors?

A

homodimeric pair, heterodimeric pair(two receptors recognize each other and you have the activation of gene transcription.

92
Q

how is thyroid hormone transferred across the cell membrane?

A

because of its polar nature, it requires a carrier mediated transporter

93
Q

what is significant about the cholera toxin?

A

Toxin catalyzes the adenosine diphosphate (ADP-) ribosylation of G-alpha-s (an allosteric covalent modification) thus remaining constitutively active.(modification of g-protein because of the ribosylation making the alpha subunits active all the time.)cAMP is generated from the adenylate cyclase and this signaling modifies activity of chloride transport or CFTR(usually site of deficiency) and so chloride balance is lost

94
Q

why is chloride important in the mechanism of the way cholera toxin works?

A

Cl- controls water balance and so because cAMP levels are always high this effects the concentration of Cl-Physiological result: Too much Cl- transported out of cellWater moves out to balance this osmotic change. Excess extracellular water = watery diarrhea

95
Q

what modification does cholera toxin make that causes the alpha subunit to be active all the time?

A

Cholera toxin causes ADP-ribosylation of Gs alpha subunit. Makes alpha subunit active all the time, independent of GTP/GDP

96
Q

what does adenylate cyclase recognize again?

A

the GTP bound g-protein and the effect is increased production of cAMP

97
Q

what example can we name that has the similar effect but different mechanism?

A

pertussis toxin

98
Q

how does an inhibitory G protein work?

A

when bound they shut active site down on the adenylate cyclase (ADP ribosylation) and production of cAMP is slowed; the types of receptors are also different. In a normally functioning cell, inhibition and stimulation is important

99
Q

so how does the inhibitory G protein in the pertussis toxin work?

A

-Normally AC activity is balanced by an inhibitory G-protein, Gi -PTX causes ADP-ribosylation of Gi causing it to stay in the GDP form = inactive toward AC-In a similar fashion, pertussis toxin affects AC function…but by removing AC inhibition by an inhibitory G protein. Under normal conditions, an inhibitory G protein G-alpha-i will bind to AC and inhibit it, to help control the amount of cAMP AC produces. Pertussis toxin inhibits this G protein, so that G-alpha-i can’t release GDP and bind GTP, so it is never activated to bind to AC, so AC does not receive the signal to be inhibited.

MABS Biochemistry (54 decks)

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