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Biochemistry 2 > Biosignaling > Flashcards

Biosignaling Flashcards

1
Q

What is a signal?

A

Non-covalent interaction between ligand and receptor

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2
Q

Signals that cells receive from the environment beyond the plasma membrane

A 
Antigens
Hormones
Neurotransmitters
Light
Touch
Pheromones
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3
Q

What is a receptor

A

A membrane-bound or soluble protein or protein complex, which exerts a physiological effect (intrinsic effect) after binding its natural ligand

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4
Q

Explain a feature if signal transduction: specificity

A
  • Complementarity ( lock and key model)
  • Non-covalent bond (not permanent interaction)
  • Tissue specific receptor (when ligand goes all over the body, but binds only to a specific cell and produce a specific effect)
  • Tissue specific receptor target (receptors are more than 1 place and they have different target)
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5
Q

Tissue-specific receptor target: Adrenalin

A

Adrenalin cells are in the pancreas( glycogen break down) and in the adipose cells( release of FA)

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6
Q

Explain the concept of amplification

A

When enzymes activate enzymes, the number of affected molecules increases geometrically in an enzyme cascade

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7
Q

What is modurality as features of signal transduction

A

Signaling has domains ( motives), parts of the protein that has specific function in the signaling, they do not need to be catalytic, they can perform physical function - better fitting
It increases the possibility of the response

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8
Q

Explain desensitization/adaptation

A

Though the ligand is still there, there is no response any more. You stop getting the response , because you get used to it
EG. smell, bright light ot dark light,skin sensation

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9
Q

What is intergration as a feature of signal transduction

A

When two signals have opposite effects on a metabolic characterstics such as the concentration of a second messenger, or the membrane potential, the regulatory outcome results from the integrated input from both receptors
The actual response depends on the sum of the ligands

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10
Q

What is the second messenger and the difference between second and first messenger

A

Second messenger-an intracellular substance (as cyclic AMP) that mediates cell activity by relaying a signal from an extracellular molecule (as of a hormone or neurotransmitter) bound to the cell’s surface
First messenger- an extracellular substance (as the hormone epinephrine or the neurotransmitter serotonin) that binds to a cell-surface receptor and initiates intracellular activity

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11
Q

What is localization as a feature of signal transduction

A

When the enzyme that destroys an intracellular message is clustered with the message producer, the message is degraded before it can diffuse to distant points, so the response is only local and brief

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12
Q

4 types of receptors that we study

A
  • G protein -coupled receptor(GPCR)
  • Receptor enzyme tyrosine kinase (RTKase)
  • Gated ion channel
  • Nuclear receptor
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13
Q

Why GPCRs are important

A

About 50% of all drugs target GPCR-prozac, zantac

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14
Q

What are essential components for GPCR

A

-a plasma membrane receptor
- a G protein that cycles between active (GTP-bound) and inactive
(GDP-bound) forms
- an effector enzyme (or ion channel) in the plasma membrane that is
regulated by the activated G protein
-An extracellular signal such as a hormone, growth factor, or
neurotransmitter is the “first messenger” that activates a receptor from outside the cell

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15
Q

Explain the general principle of work of GPCRs

A

When the
receptor is activated, its associated G protein exchanges its bound GDP for a GTP from the cytosol.
The G protein then dissociates from the activated receptor and binds to the nearby effector enzyme,
altering its activity. The effector enzyme then causes a change in the cytosolic concentration of a low
molecular weight metabolite or inorganic ion, which acts as a second messenger to activate or
inhibit one or more downstream targets

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16
Q

Explain in detail what happens in epeniphrin (adrenalin) signaling

A

GPCR receptor

1 )Epinephrine action begins when the hormone binds to a
protein receptor in the plasma membrane ( beta-adrenergic receptor)
2) The binding of epinephrine to a site on the
receptor promotes a conformational change in
the receptor’s intracellular domain that affects its interaction with an associated G protein, promoting
the dissociation of GDP and binding of GTP from the cytosol
3) Gsα, with its bound GTP, moves in the plane of the
membrane from the receptor to a nearby molecule of adenylyl cyclase
4) Adenylyl cyclases catalyzes the formation of cAMP
5) Cyclic AMP, the second messenger, activates protein kinase A or PKA

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17
Q

What is an agonist and antagonist

A

Agonists are molecules (natural ligands or their structural analogs) that bind to a
receptor and produce the effects of the natural ligand; antagonists are analogs that bind the receptor
without triggering the normal effect and thereby block the effects of agonists, including the natural
ligand.

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18
Q

Beta adrenergic receptor can be found in

A

muscle, liver, and adipose tissue

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19
Q

The structure of G protein

A

For all GPCRs, the G protein
is heterotrimeric, composed of three different subunits: α, β, and γ. In GPCR, it is the α subunit that binds GDP or GTP and transmits
the signal from the activated receptor to the effector protein.

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20
Q

Types of G proteins

A

Gs-> stimulatory

Gi-> inhibitory

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21
Q

How GPCRs are regulated?

A

The stimulation by Gsα is self-limiting; Gsα has intrinsic GTPase activity that inactivates Gsα by
converting its bound GTP to GDP, because G protein is a kinase itself.
But the time when it is bond to GTP is enough to activate adenylyl cyclase

remove the second messenger: cAMP is hydrolyzed to 5′-AMP (not
active as a second messenger) by cyclic nucleotide phosphodiesterase by the process of hydrolyses ( just the ring structure is opened)

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22
Q

How does GPCR comes back to the state before activation

A

The now inactive Gsα dissociates from adenylyl
cyclase, rendering the cyclase inactive. Gsα reassociates with the βγ dimer (Gsβγ), and inactive Gs is
again available to interact with a hormone-bound receptor

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23
Q

In the inactive state G protein is always bound to

A

GDP

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24
Q

What is the most widespread second messenger

A

cAMP

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25
The structure of cAMP and how it is formed
cAMP foromed form ATP by adenylyl cyclase that removes two phosphates and cycles at carbon 3 and 5 with the phosphate ATP- adenosine +three phosphate+ribose
26
The name second messenger is usually given to
Non-proteins, that take message form one place to another
27
PKA units
PKA is always in dimer form AKAP ( A kinase anchoring protein) hold two parts of PKA One part of PKA: catalytic subunit, regulatory subunit
28
How does PKA get activated
Inhibitory subunits are always bound to regulatory subunit. When [cAMP] rises in response to a hormonal signal, each Regulatory subunit binds two cAMP molecules and undergoes a dramatic reorganization that pulls its inhibitory sequence away from the Catalytic subunit, opening up the substrate-binding cleft and releasing each C subunit in its catalytically active form
29
Pathways that are regulated with GPCR signaling and by what protein
Glycogen synthesis-glycogen synthase Glycogen breakdown-phosphorylase b kinase Glycolysis-pyruvate kinase Pyruvate to acetyl -CO-A->pyruvate degydrigenase complex Triacylglycerol mobilization and fatty acid oxidation->hormone-sensitive lipase Glycolysis/glucoenogenesis->phosphofructokinase 2/fructose 2,6-biphosphotase
30
What are GTP-GDP exchange factors
Factors that help to exchange GTP to GDP . They are rhodopsin (Rh) and β-adrenergic receptors (AR).
31
What is downstream effector enzymes
cGMP phosphodiesterase (PDE), adenylyl cyclase (AC), and Raf.
32
GTPase activator proteins are
GAPs(GTPase activator proteins) and regulators of G protein signaling (RGSs) -Regulators of G protein Signaling
33
What is desentization?
signal termination | damps the response even while the signal persists
34
describe the desentization of epinephrine receptor
When the receptor remains occupied with epinephrine, β-adrenergic receptor kinase, or βARK , phosphorylates several Ser residues near the receptor’s carboxyl terminus, which is on the cytoplasmic side of the plasma membrane. PKA, activated by the rise in [cAMP], phosphorylates, and thereby activates, βARK. βARK is then drawn to the plasma membrane by its association with the Gsβγ subunits and is thus positioned to phosphorylate the receptor. Receptor phosphorylation creates a binding site for the protein βarr and binding of BARR blocks the sites in the receptor that interact with the G protein Barr receptor is taken inside of the cell by the process of endocytosis, then this portion of the membrane is cleaved into small vesicle within the cell, As soon as the receptor comes into the cell , it is no longer available for the ligand, Barr is dissociated from the receptor and now fresh receptor is ready to function, non-phosphorylated, non-ligand bonded receptor
35
What gets phorsphorylated during desentization process?
Ser residues in on the intracellular side of the receptor
36
What signals use cAMP as a second messenger
``` Corticotropin Dopamine Epinephrine Follicle-stimulating Glucagon Luteinizing hormone Melanocyte-stimulating hormone Odorants Prostaglandins Serotonin Somatostatin Tastants (sweet,bitter) ```
37
Prostaglandin has Gi reseptor. If the cell has prostaglandin and epinephrin receptor at the same time, what does it do?
The possibility of signal integration, of the cell simultaneously exposed to adrenaline(Gs) and prostaglandins(Gi) , the result depends on , who is more ( prostaglandins or adrenaline )
38
What is AKAP and what does it do
A kinase anchoring protein It ensures that the signal stays in one palce ( localized) holds PKA and adenylyl cyclase at one place, so it allows the signal to stay in this location
39
What does cannibis do
It has Gi receptor that inhibits cAMP production
40
Second broad class of GPCRs are
phospholipase C (PLC)
41
What G protein stimulates phospholipase C ?
Gq alpha | It has the same mechanism of activation as gs alpha
42
How does phospholipase C function
It catalyzes cleavage of the membrane of PIP2 to IP3 and diacylglycerol
43
How do we get IP3 from PIP 2
PLC converts PIP2 to IP3 by breaking PIP2 at carbon 1 and adding an extra phosphate group on that carbon. Diacylglycerol is detached from carbon 1
44
Who does act as the second messanger in PLC pathway
IP3
45
What happens after the conversion of PIP2 to IP3
IP3 a water-soluble compound, diffuses from the plasma membrane to the endoplasmic reticulum (ER), where it binds to specific IP3-gated Ca2+ channels, causing them to open. Ca2+ rushes into the cytosol , and the cytosolic [Ca2+] rises sharply
46
The effects of elevated concentration of calcium in the cytoplasm
One effect of elevated [Ca2+] is the activation of protein kinase C (PKC; C for Ca2+). Diacylglycerol cooperates with Ca2+ in activating PKC, thus also acting as a second messenger. Phosphorylation of cellular protein by protein kinase C produces some of the cellular responses to the hormone
47
Neurotransmitters act through
GPCR, PIP2 and calcium channels
48
How many times the protein passes thorugh the membrane in hormone specific protein
7
49
The major pathways of RTKases
MAPK | PIP3
50
Insulin receptor functions ____
as a dimer
51
explain MAPK pathway on the example of insulin receptor
Initiation: receptor and ligand interaction, insulin binds to insulin receptor The portion that is( cytoplasmic domain - inside the cytoplasm) gets phosphorylated 2) This phosphorylation leads to another phosphorylation of insulin receprtor (IRS-1) 3) IRS-1 acts as a docking protein( adaptor ) for GRB-2 , a cascade of adaptor proteins SOS binds to GRB 2, then to Ras,causing GDP release and GTP binding to Ras. Activated Ras binds and activates Raf-1 4) They come together and form a complex of proteins 5) MEK gets phosphorylated ->activated 6) MEK phosphorylates ERK 7) Phosphorylated ERK moves into the nucleus, where ( as a kinase) activates transcription factors ELK-1-> phopshorylated ELK-1 binds to SRF1-> transcription->translation-> protein
52
How can you remember the sequence of MAPK pathway
``` rigRRmet Receptor IRS Ras Raf-1 MEK ERK transcription ```
53
Signaling through PIP3
1) Ligand binding to the receptror, and it phosphorylayes IRS-1 2) IRS-2 acts as a docking protein 3) IRS-2 phosphorylates allows PI3K to connect 4) PI3K converts PIP2 to PIP3 ( not a cleavage mechanism like in GPCR) 5) PIP3 allows to dock PKB, which is activated by phosphorylation 6) Protein kinse B( PKB) phosphorylate GSK3 , inactivating it , now GS kinase cannot add phosphate to inactivate GS (glycogen synthase), so synthesize of glycogen occurs ( REMOVAL OF INACTIVATOR) 7) PKB helps in opening GLUT4 and helps in bringing glucose inside the cell
54
The protein kinases MEK and | ERK are activated by phosphorylation of
both a Thr and a Tyr residue
55
When does glycogen synthase function
When it is not phosphorylated, so when GSK3 is inactive
56
What does PI3K do
phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) by the transfer of a phosphoryl group from ATP.
57
PKB phosphorylates what AA on GSK3
Ser or Thr
58
The extracellular domain in RTKases is
unique to each type of receptor, reflecting the different growth-factor specificities
59
Cross talk and intregration between GPCR and RTK
For example, the RTKase directly phosphorylates two Tyr residues in the cytoplasmic tail of a β2-adrenergic receptor, and PKB, activated by insulin , phosphorylates two Ser residues in the same region. Phosphorylation of these four residues triggers the uptake in the cytoplasmof the β2-adrenergic receptor, taking it out of service and lowering the cell’s sensitivity to epinephrine A second type of cross talk between these receptors occurs when P –Tyr residues on the β2-adrenergic receptor, phosphorylated by RTKase, serve as nucleation points for SH2 domain–containing proteins such as Grb2 ( a protein cascade)-> . Activation of the MAPK ERK by insulin-> altered gene expression
60
Kinase can add phosphate to specific AA
Serine(Ser or S) Threonine(Thr or T) Tyrosine (Tyr or Y)
61
AA are phosphorylated by
Transfer of phosphate group from ATP
62
Resting membrane potential
-70 -- -50 mV
63
Excitable cells play an important role in
nerve conduction, muscle contraction, hormone secretion, sensory processes, and learning and memory.
64
Escitable cells are
they can detect an external signal, convert it | into an electrical signal (specifically, a change in membrane potential), and pass it on.
65
How do excitable cell pass on the excitement
ion channels, signal transducers that provide a regulated path for the movement of inorganic ions such as Na+, K+, Ca2+, and Cl− across the plasma membrane in response to various stimuli. these ion channels are “gated”: they may be open or closed, depending on whether the associated receptor has been activated by the binding of its specific ligand (a neurotransmitter, for example) or by a change in the transmembrane electrical potential.
66
What does maintain the cell in the polarized state? and establishes the membrane potential
Na+K+ATPase
67
Three membrane potential status
Polarized (The difference between the charge outside and inside, resting state) Depolarized( when the gated channels are opened and some of the ions move, the inside becomes a little more positive than the outside) Hyperpolarized ( The membrane becomes more negative)
68
How is the mebrane potential established
it creates a charge imbalance across the plasma membrane by carrying 3 Na+ out of the cell for every 2 K+ carried in. The action of the ATPase makes the inside of the cell negative relative to the outside.
69
The direction of spontaneous ion flow across a polarized membrane is dictated by
the electrochemical potential of that ion across the membrane, which has two components: the difference in concentration of the ion on the two sides of the membrane, and the difference in electrical potential
70
When ion gated channels are opened, where will the ions go
Na+ will go inside the cell ( because inside it is negative and plus less sodium ions) - Ca will go inside - K will go outside - Cl will go outside , because inside it is negative ( against the chemical gradient)
71
Explain how the signal is transmitted along the axon
Initially, the plasma membrane of the presynaptic neuron is polarized (inside negative) through the action of the electrogenic Na+K+ ATPase, which pumps out 3 Na+ for every 2 K+ pumped in 1 A stimulus to this neuron causes an action potential to move along the axon , away from the cell body. The opening of a voltage-gated Na+ channel allows Na+ entry, and the resulting local depolarization causes the adjacent Na+ channel to open, and so on. 2 A split second after the action potential passes a point in the axon, voltage-gated K+ channels open, allowing K+ exit, which brings about repolarization of the membrane to make it ready for the next action potential. As K channels are opened right after Na channels , the signal goes only forward. 3 When the wave of depolarization reaches the axon tip, voltage-gated Ca2+ channels open, allowing Ca2+ entry. 4 The resulting increase in internal [Ca2+] triggers exocytotic release of the neurotransmitter acetylcholine into the synaptic cleft. 5 Acetylcholine binds to a receptor on the postsynaptic neuron , causing its ligand-gated ion channel to open. 6 Extracellular Na+ and Ca2+ enter through this channel, depolarizing the postsynaptic cell. events
72
When acetylcholine binds to the receptor it ____ and it allows ____ and then shortly ___
Makes a conformational change, The influx of cations Intrinsic mechanism to close
73
Serotonin and glutamine receptors are __ and glycine is ___
Serotonin and glutamate trigger the opening of cation (Na+, K+, Ca2+) channels, whereas glycine opens Cl−-specific channels
74
Caffeine is
Anatgonist, blocking adenosine receptor
75
What is the normal function of adenosine and ow caffeine works against it?
Inhibits other neurons, reduces the excretion of exciting neurotransmitters and decrease the effect of dopamine. Thus, reduces the alertness and induces sleep From morning to evening, adenosine concentration increases form morning to evening Caffeine blocks adenosine , thus increasing alertness
76
Who can participate in nuclear receptors?
Lipid soluble( because they need to get through the membrane ) : steroids, thyroid hormones, retinoic acid , vitamin D
77
What is the "problem" of nuclear receptors
They are rather slow
78
Explain the action nuclear receptors
1) Steroid hormones , too hydrophobic to dissolve readily in the blood, are transported on specific carrier proteins from their point of release to their target tissues. 2)In target cells, these hormones pass through the plasma membrane and nuclear membrane by simple diffusion and bind to specific receptor proteins in the nucleus . 3)Hormone binding triggers changes in the conformation of a receptor protein and becomes homo- or heterodimers so that are capable of interacting with specific regulatory sequences in DNA called hormone response elements (HREs), thus altering gene expression . They bind to the specific region, depending on the ligand 4) This binding stimulates the proteins around that will activate or suppress the rate of mRNA formation It can inhibitory or increasing the rate

Biochemistry 2 (17 decks)

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