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BIO 317 > Nobel Prizes > Flashcards

Nobel Prizes Flashcards

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1
Q

Who did Gilman work with initially?

A

Rall (Sutherland’s collaborator)

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2
Q

What did Gilman work with initially?

A

Cyclic nucleotides (cAMP)

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3
Q

What research question was Gilman studying?

A

How are receptors coupled to adenylyl cyclase

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4
Q

What was the issue with Rodbell’s experiments of a transducer?

A

Other researchers could not replicate his results

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5
Q

How come other researchers could not replicate Rodbell’s results?

A

They did not have access to the purified membranes that he did

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6
Q

What was the turning point of Gilman’s research?

A

Experiments with cyc- mutants

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7
Q

What was the most interesting cyc- mutant that Gilman studied?

A

Uncoupled receptor and AC, had both components working, but no cAMP response

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8
Q

What did the blots that Gilman did reveal?

A

Purification of aGs and bGs

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9
Q

What is special about fluoride activation of aG?

A

Requires a cofactor (Al3+)

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10
Q

Why does fluoride need an aluminium cofactor to activate aG?

A

AlF4 mimics GTP for activation of aGs

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11
Q

What does ARF stand for?

A

ADP-ribosylation factor

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12
Q

What does ARF do?

A

Required for cholera to bind NAD to aGs

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13
Q

What was the moral of Gilman’s experiments with Gi?

A

Never throw anything away (found Gi through leftover samples)

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14
Q

How were different families of G-proteins discovered?

A

Parallels between vision transduction and adrenaline were discovered

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15
Q

What was the evolutionary relationship between the alpha subunits of G-proteins?

A

They were distinct but related

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16
Q

What was the evolutionary relationship between the beta subunits of G-proteins?

A

They were very similar or identical

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17
Q

What are the groups of G-proteins, and their size?

A

Small Gs group, large Gi group, Gq, and G12

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18
Q

What is the general function of G-proteins?

A

Function as switches and timers

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19
Q

What is the speed of GTPase activity?

A

Fairly slow catalysis - sec to min

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20
Q

If there is no GTP, what complex of G-protein is stable?

A

Hormone-receptor-aG complex

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21
Q

What does aG have a high affinity for?

A

GTP

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22
Q

True or false: many G-proteins undergo lipid covalent modifications

A

True: these modifications help for affinity of a subunit to beta/gamma complex

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23
Q

What big biochemical breakthrow allowed for studying the properties of G-protein subunits?

A

In transfecto (adding DNA to cells for expression)

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24
Q

What was the advantage of using In transfecto to study G-protein subunits?

A

Could see their function without other G-protein subunits present

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25
Q

What is gusducin?

A

A G-protein found selectively in taste buds

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26
Q

What protein is gusducin similar to?

A

Transducin

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27
Q

What does the beta/gamma subunit function as?

A

Noise suppressor

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28
Q

How does the beta/gamma subunit function as a noise suppresor?

A

Helps prevent random GDP dissociation

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29
Q

What is the functional advantage of utilizing G-proteins?

A

Allows for large amplification, and convergence or divergence

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30
Q

How is convergence seen in G-protein signaling?

A

Many receptors can converge on one G-protein, and many G-proteins can converge on one effector

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31
Q

How is divergence seen in G-protein signaling?

A

A single receptor can activate many G-proteins, and one G-protein can activate more than one effector

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32
Q

What is the practical advantage of utilizing G-proteins signaling?

A

Highly customized signaling repertoire with relatively few components

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33
Q

What are the most versatile chemical sensors?

A

GPCRs

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34
Q

What is the general pathway of a GPCR?

A

GPCR detects extracellular agonist, activates G-protein, modulates downstream effectors

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35
Q

True or false: one receptor can only couple to one G-protein

A

False: Beta 2 AR can couple to both aGs and aGi in cardiac myocytes

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36
Q

What is ligand efficacy?

A

The effect of a ligand on the structure and biophysical properties of a receptor

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37
Q

What is the largest group of targets for drug discovery?

A

GPCRs

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38
Q

Where did the first structural insights of GPCRs come from?

A

Rhodopsin and bets 2 AR

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39
Q

What is the signature of a GPCR?

A

7 transmembrane topology

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40
Q

How were the domains for ligand binding and G-proteins identified?

A

Using beta 2 AR and alpha 2 AR

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41
Q

Why was beta 2 AR a good model system?

A

Had many structural studies through mutagenesis, and there were a diversity of ligands present for different effects

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42
Q

What was the problem of doing biophysical studies on beta 2 AR?

A

Expression and purification of unstable membrane proteins

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43
Q

How was beta 2 AR purified and expressed for biophysical studies?

A

Inserted a cleaveable signal sequence

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44
Q

What was used to characterize mechanisms of activation of beta 2 AR?

A

Fluorescence spectroscopy

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45
Q

What is a rheostat?

A

A device that adjusts a value along a range

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46
Q

How are GPCRs molecular rheostats?

A

They have a range of conformations to allow for specific ligand binding

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47
Q

What is meant by a “ligand specific conformation” for GPCRs?

A

A specific ligand causes a specific conformation (out of a range) of the GPCR

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48
Q

Why did rhodopsin give the first insight into GPCRs?

A

Relatively high stability, and natural abundance

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49
Q

What were the 2 impediments to crystallography of beta 2 AR?

A

Dynamic character, and small polar surface area for crystal lattice contact

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50
Q

How were the problems with crystallography of beta 2 AR overcome?

A

Used antibodies and protein engineering to crystallize the inactive state

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51
Q

What was the challenge of crystallography of active beta 2 AR?

A

Agonists alone do not fully stabilize beta 2 AR

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52
Q

What is needed to fully stabilize beta 2 AR?

A

Gs

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53
Q

What was used to stabilize active beta 2 AR for crystallography?

A

Nanobodies

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54
Q

True or false: there is one active state of beta 2 AR

A

False: conformational changes are not consistent with a single active state (sequential)

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55
Q

Which transmembrane unit undergoes the largest changes in response to agonists?

A

TM6

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56
Q

Why does beta 2 AR have little polar surface?

A

It is largely a transmembrane protein, and thus needs large hydrophobic regions

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57
Q

What maintains the inactive state of beta 2 AR?

A

Packing of conserved amino acids

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58
Q

What is required to accommodate agonist binding in beta 2 AR?

A

Rearrangement of conserved amino acids

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59
Q

What were the two postulates of receptors?

A

They interact with stimuli, and act on effectors to alter function

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60
Q

True or false: the existence of receptors was generally accepted

A

False: there was a lot of skepticism surrounding receptors

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61
Q

What was radioligand binding used for (in terms of studying GPCRs)?

A

Regulation, subtypes, and theories of mechanisms

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62
Q

What was the “Rosetta Stone” of GPCR families?

A

Purification of the first four (rhodopsin, adrenaline, etc.)

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63
Q

How could Gi be converted into Gs?

A

Replacing the third cytoplasmic loop

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64
Q

How is homeostasis present in GPCR function?

A

Desensitization (stop reacting to signal)

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65
Q

What is BARK?

A

beta-adrenaline receptor kinase, now called GRK2

66
Q

How many enzymes are in the GRK family?

A

7

67
Q

How many groups are there in the GRK family?

A

3

68
Q

What are the groups in the GRK family?

A
  1. 1,7
  2. 2,3 (BARK 1,2)
  3. 4,5,6
69
Q

How are the GRKs distrubuted in the body?

A

GRK 1 and 7 are found only in the retina; GRK 2, 3, 5, 6 and ubiquitously expressed

70
Q

What type of kinases are GRKs?

A

Serine/threonine kinases

71
Q

How are GRKs translocated to the plasma membrane?

A

Interactions with beta/gamma G

72
Q

How is arrestin binding similar and different in different GPCRs?

A

Same mechanisms, but with great specificity for the particular receptor

73
Q

How are the arrestins distributed in the body?

A

Arrestin 1 and X arrestin are in the retina, beta-arrestin 1 and beta-arrestin 2 are ubiquitously expressed

74
Q

What is the structure of arrestin?

A

Many antiparallel beta sheets with a polar core

75
Q

True or false: PKA and PKC are receptor specific

A

False: they are fairly general, and not receptor specific

76
Q

How does desensitization of GPCRs occur?

A

Receptor phosphorylation, and arrestin binding

77
Q

What motif can function as a signal transducing system (in the GPCR system)?

A

Arrestin-GRK system

78
Q

What are the three functions of beta-arrestin?

A

Desensitization, internalization (endocytosis), and signaling

79
Q

What does beta-arrestin binding link to?

A

MAP kinase pathway, or clathrin coated pit endocytosis

80
Q

What do biased agonists do?

A

Stabilize particular active form, stimulating some responses and not others

81
Q

What pathways can be biased in the GPCR system?

A

G-protein pathway, or beta-arrestin pathway

82
Q

What are the characteristics of beta-arrestin signaling?

A

Diverse, uses similar pathways to G-proteins, and it has distinct cellular effects

83
Q

What governs the fraction of receptors with bound ligand?

A

Ligand concentration

84
Q

What is another name for GPCRs?

A

7TMs

85
Q

What does 7TM stand for?

A

7 transmembrane (regions)

86
Q

What was the classical receptor theory based on?

A

Law of mass action and dose-response data

87
Q

What was used to prove the existence of receptors?

A

Radioactively labelled agonists

88
Q

Why are receptors that bind to diffuseable ligands harder to purify?

A

They are found in smaller amounts

89
Q

What is the same across GPCRs?

A

Same manner of signal transmission

90
Q

How many conformations do GPCRs have?

A

A large number, ranging from inactive to active

91
Q

What shape do the helices resemble?

A

Rods

92
Q

Where are the helices found in a GPCR?

A

In the plasma membrane (7 transmembrane regions)

93
Q

What is the mechanical motion of the GPCR when an agonist binds?

A

Grips bundle at one end, opens up like a rose bouquet at the other end

94
Q

How big is the structural change on the ligand side of the GPCR?

A

Small change

95
Q

How big is the structural change on the intracellular side of the GPCR?

A

Large change

96
Q

What is the holy grail of GPCR research?

A

High resolution picture of active ternary complex (receptor, ligand, and G-protein)

97
Q

How stable is the ternary complex (GPCRs)?

A

Not very stable

98
Q

Why is there inherent instability of the ternary complex (GPCRs)?

A

Able to activate many G-proteins

99
Q

What 5 biochemical strategies were used to visualize GPCRs?

A
  1. Apyrase treatment (ATP -> ADP -> AMP)
  2. Special detergent
  3. Nanobody stabilization (instead of G-protein)
  4. Covalent agonist binding (keep agonist)
  5. Protein engineering (reduce mobility of helices)
100
Q

What is an agonist (in terms of GPCRs)?

A

A molecule that binds to GPCR and stabilizes a conformation that activates a G-protein

101
Q

What is an inverse agonist (in terms of GPCRs)?

A

A molecule that binds to and stabilizes an inactive conformation of the GPCR

102
Q

What is an antagonist (in terms of GPCRs)?

A

A molecule that competes with agonists to bind to and block binding sites on GPCR

103
Q

How does an antagonist block GPCR signaling?

A

Prevents conformational change that activates G-protein

104
Q

What are the design criteria of developing a new drug?

A

High specificity, high efficacy, and few side effects

105
Q

What is the importance of the biochemical techniques used to purify AR?

A

Can be used to purify other 7TM receptors

106
Q

True or false: the same GPCR can signal through different intracellular pathways depending on the ligand

A

True: there are different active forms based on the ligand

107
Q

Why can a GPCR signal through different intracellular pathways depending on the ligand?

A

Relative flexibility of receptor in membrane (different active and inactive forms)

108
Q

True or false: the same 7TM receptor can be both G-protein dependent and G-protein independent

A

True: this is done through biased signaling

109
Q

How does nature and nurture interact?

A

Mutually and synergistically

110
Q

What broad issues did Rodbell study?

A

Broad issues of biological communication

111
Q

What laid the foundation for the transducer theory?

A

AC

112
Q

What was the critical lesson by Rodbell?

A

Check sources, and never interpret a hyperbolic curve (describes behavior of entire universe)

113
Q

What was needed to measure the pharmacology of hormone receptors (in Rodbell’s time)?

A

Indirect tests

114
Q

What was the central question studied by Rodbell (with fat cells)?

A

Do all hormones operate on the same enzyme, or is it coupled to separate cyclases?

115
Q

What was Rodbell’s argument regarding receptors and enzymes?

A

Multiple receptors interacted with a common catalytic unit

116
Q

What was the common structural element of the transducers?

A

A structure that converted MgATP into cAMP

117
Q

How was it discovered that lipids were somehow involved in structural interactions?

A

Receptors were sensitive to agents that affected membrane structure

118
Q

What is meant by “too many angels on a pinhead”?

A

Hard to believe that several hormones were structurally annealed to the same enzyme

119
Q

What influenced transducer theory?

A

Informational processing (cybernetic theory)

120
Q

What does a transducer do (in cybernetic theory)?

A

Couples discriminator and amplifier

121
Q

What does a discriminator do (in cybernetic theory)?

A

Decides a state

122
Q

What is the discriminator in biology?

A

Receptor

123
Q

What does an amplifier do (in cybernetic theory)?

A

Amplify a response

124
Q

What is the amplifier in biology?

A

AC (makes cAMP to amplify signal)

125
Q

What system do adipocytes have?

A

Multiple receptor-AC system

126
Q

Why did Rodbell move from a fat system to a liver system?

A

Simpler system (multiple receptor AC-system to just glucagon specific)

127
Q

What do guanine nucleotides do?

A

Lower affinity of receptor for hormone

128
Q

How long was the system active with non-hydrolyzable GTP?

A

Three days at room temperature

129
Q

What must the transducer do (in a biological sense after Rodbell’s experiments)?

A

Have capacity to hydrolyze GTP

130
Q

What is the limiting step in G-protein signaling?

A

Release of Pi (not hydrolysis)

131
Q

What is the difficult problem in membrane biology?

A

Understand how components are organized in the membrane

132
Q

What questions are central to the difficult problem in membrane biology?

A

How are proteins distributed to obtain efficiency and rapidity

133
Q

What did the irridation studies suggest?

A

Disaggregation theory (based on lower functional size)

134
Q

What components are in excess: G-proteins or receptors?

A

G-proteins (10:1)

135
Q

What helps separate aG from beta/gamma G?

A

Interactions of enzyme, Mg, and GTPase

136
Q

What are the similarities between G-proteins and cytoskeletal proteins?

A

Similar functions, substrates, activators, regulation, etc.

137
Q

What do G-proteins sense?

A

Chemical signals

138
Q

What do tubulin / actin sense?

A

Mechanical signals

139
Q

What was the prevailing theory in Sutherland’s time regarding hormone action?

A

Hormone action could not be studied in the absence of cell structure

140
Q

What was the inspiration for Sutherland’s studies?

A

Biosynthesis of urea

141
Q

What is necessary for scientific progress?

A

Young / talented investigators, with free exchange of ideas

142
Q

Why was glycogen breakdown Sutherland’s model of interest?

A

It was rapid, large, and reproducible

143
Q

What is the rate-limiting step in glycogen breakdown?

A

Phosphorylase

144
Q

How did hormones improve the rate-limiting step in glycogen breakdown?

A

Increased phosphorylase activity

145
Q

What was the inactivating enzyme in glycogen breakdown?

A

Phosphatase

146
Q

What was the heat stable factor that activated phosphorylase?

A

cAMP

147
Q

What was found about AC in Sutherland’s experiments?

A

Converted ATP > cAMP, widely distributed

148
Q

What was found about phosphodiesterase in Sutherland’s experiments?

A

Converted cAMP -> AMP, widespread occurance of CAMP

149
Q

What is the mechanism of action for glucagon and epinephrine?

A

Increased cAMP by stimulated AC (not inhibiting PDE)

150
Q

Where was AC originally thought to be located?

A

In the nucleus

151
Q

How was the idea that AC was in the nucleus disproved?

A

Fragmentation of the membrane also fragmented AC

152
Q

Why do cells have different responses to cAMP?

A

Different cells have different enzymes

153
Q

What was Sutherland’s 4 criteria for his studies involving cAMP?

A
  1. AC should be stimulated
  2. cAMP levels should change
  3. PDE inhibitors should add synergistically
  4. Effect should be mimicked with external cAMP
154
Q

What was done to make cAMP able to enter the membrane?

A

Make it more lipid soluble

155
Q

Which cAMP derivative gave a higher response in Sutherland’s studies?

A

Lipid-soluble (perhaps due to penetration of cell membrane)

156
Q

What was the significance of Sutherland’s rat heart studies?

A

Measured cAMP levels and a mechanical / functional response (not chemical)

157
Q

What is interesting about slime molds?

A

cAMP is used as a first messenger, not a second messenger

158
Q

What are the two naturally occurring cyclic nucleotides?

A

cAMP and cGMP

159
Q

What are the differences between AC and GC?

A

GC is more soluble, requires Mn2+, and is not stimulated by fluoride

160
Q

True or false: the biological role of cGMP is the same as cAMP

A

False: they have different roles in biology

BIO 317 (27 decks)

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