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Mechanism of Disease > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

enzymes which place phosphates on other molecules

A

kinases

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2
Q

enzymes which remove phosphates from molecules

A

phosphatases

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3
Q

enzymes that place acetyl groups on lysines

A

acetyltransferases

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4
Q

enzymes which remove acetyl groups

A

deacetylase

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5
Q

ubiquitin

A

molecule that when attached to a protein, marks it for degradation

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6
Q

ubiquitin ligase

A

enzyme complex that places ubiquitin onto a specific lysine residue on a protein

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7
Q

how is ubiquitin arranged?

A

as a chain

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8
Q

what is proteasome

A

multi-subunit protein complex (1% of total protein) that uses ATP to provide energy to unfold & digest protein into smaller peptide molecules

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9
Q

epigenetics

A

changes in gene expression caused by certain pairs of DNA or RNA to be turned on or turned off by chemical reactions

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10
Q

how is cell type determined?

A
  1. what regions of chromatin are open

2. what transcription factors are active

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11
Q

What are the functions of the cell membranes

A
  • defines the cell
  • separates compartments
  • controls movement of molecules
  • generation of gradients
  • scaffold for assembling large molecular complexes
  • resource for materials
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12
Q

What is important about cell compartment separation by membranes?

A

allows specialized chemical reactions to proceed

allows diverse chemical reactions to occur in close proximity

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13
Q

How does a cell membrane control movement of molecules?

A
  • uses specialized pumps & channels that span the membrane to get nutrients and eliminate waste
  • uses receptors to get and give information
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14
Q

what kinds of gradients does a cell membrane generate?

A 
voltage gradients (ions) in nerve cells (to power electrical signaling)
concentration gradients (to drive pumps)
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15
Q

what are some examples of molecular complexes that are assembled using membrane scaffolding?

A

ATP in mitochondria
photoreceptors (detecting light)
signal transduction events

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16
Q

What is the structure of a phospholipid?

A

fatty acid chains (acyl groups) (2) attached to glycerol (bridge) attached to polar head group
amphipathic

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17
Q

What kind of group is a fatty acid

A

acyl group

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18
Q

How do fatty acids hide from water?

A

create a micelle or a bilayer (head groups always facing out towards water)
form spontaneously
make a hydrophobic barrier that prevents charged molecules from crossing from one side to the other

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19
Q

what are the properties of a phospholipid bilayer?

A
  • spontaneous formation in an aqueous environ. (membranes fold & seal to avoid edges)
  • forces create barriers to movement (Van der Waals forces in fatty acid & electrostatic forces in the polar head groups & water)
  • membranes are 2 dimensional solutions (lipids diffuse rapidly w/in 1 layer but can’t spontaneously flip to the other layer.
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20
Q

what are saturated & unsaturated fatty acids?

A

saturated - all possible hydrogens are bonded to carbons

unsaturated, some carbons have double bonds

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21
Q

what do saturated FAs do to membrane structure

A

interact tightly w/each other
maximum van der waals interactions
stiffer membrane

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22
Q

what do unsaturated FA do to membrane structure?

A

have a kink where carbon double bond is - blocks some of the van der wall interactions. mechanism by which melting point decreases - affects fluidity - makes membrane more fluid

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23
Q

what are other components of a cell membrane besides phospholipids?

A

sphingolipids

cholesterol

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24
Q

what is the structure of a sphingolipid?

A

uses sphingosine as the backbone instead of glycerol

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25
Q

what is the structure of cholesterol?

A

amphipathic ring structure

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26
Q

what is the 2nd largest class of membrane lipids?

A

sphingolipids

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27
Q

what is a ceramide?

A

sphingosine with one fatty acid - formed when acyl group (O=C-R C bonds to the N on NH3+) from CoA transfers onto the amine of sphingosine

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28
Q

why is ceramide important?

A

parent compound for all sphingolipids

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29
Q

What is a ganglioside?

A

a sphingolipid - like a phospholipid except it has a sugar on it instead of a head group - the sugar chain contains some information

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30
Q

what is the simplest ganglioside?

A

cerebroside - contains either a glucose or a galactose

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31
Q

what do most gangliosides terminate in?

A

sialic acids (acidic sugars) - negatively charged

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32
Q

why are the surface of most cells negatively charged?

A

b/c of the gangliosides that terminate in sialic acids which are negatively charged

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33
Q

how are gangliosides distributed in the cell membrane?

A

NOT uniformly - appear to associate w/signaling proteins

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34
Q

what is a lipid raft?

A

a signaling platform in the membrane ocean

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35
Q

what do gangliosides do w/lipid raft?

A

appear to be vital for structure of raft

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36
Q

where is the highest concentration of gangliosides found?

A

brain - where they are 6% of lipids

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37
Q

what happens to ganglioside population during development?

A

can change - also can change during tumor progression - potential to identify tumor cells by gangliosides they express & use that info to make specific targets in treatment of tumors

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38
Q

what determines blood groups?

A

gangliosides - the carbohydrate moieties on sphingolipids
all 3 blood types of 2 of the same sugars, type A and type B have a specific type of 3rd sugar and type O has neither of those two sugars

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39
Q

moiety

A

part of a molecule

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40
Q

What are some ganglioside diseases?

A

Tay-Sachs disease
Guillain-Barre syndrome
Alzheimer’s disease

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41
Q

what is the nature of ganglioside diseases?

A

there is a disruption in ganglioside breakdown

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42
Q

describe Tay-Sachs disease

A

loss of ability to remove the terminal N-acetylgalactosamine residue (genetic disease where enzyme is screwed up so that residue can’t be removed - GM2 processing defect) - weakness, retardation, death by 3 y.o. neurons get swollen w/lipid-filled lysosomes and undergo apoptosis or autophagy : processing defect - disease of the brain - something about the sugar isn’t processed right

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43
Q

describe Guillain-Barre syndrome

A

acute inflammatory disease triggered by strong infection affecting peripheral nervous system - autoantibodies produced against gangliosides damage axons - another processing defect: auto-immune disease - against gangliosides - inflammatory disease triggered by infection

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44
Q

How is Alzheimer’s disease related to gangliosides?

A

too much ganglioside GM1 contributes to aggregation of amyloid beta-protein deposits - gangliosides contribute to aggregation of amyloids - amyloid plaque

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45
Q

what does cholesterol do to cell membrane?

A

maintains cell membrane integrity and membrane fluidity

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46
Q

how physically is cholesterol inserted into the membrane?

A

hydroxyl group on end of steroid ring points out and rings & tail point into the membrane

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47
Q

How does cholesterol maintain cell membrane integrity?

A

rings interact w/neighboring fatty acid
cholesterol (ring part) is rigid so it adds firmness to membrane
decreases permeability of membrane to small water soluble molecules

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48
Q

how does cholesterol maintain membrane fluidity?

A

breaks up interactions between fatty acids - so keeps membrane from extreme states - not too fluid, not too stiff - just right, goldilocks

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49
Q

where is cholesterol found in the membrane?

A

in lipid rafts - not distributed easily - some clustering

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50
Q

what are lipid rafts composed of?

A

primarily sphingolipids (gangliosides) and cholesterol

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51
Q

where are lipid rafts found?

A

primarily in outer exoplasmic leaflet of cell membranes - connected to phospholipids & cholesterol w/in inner cytoplasmic leaflet

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52
Q

what else likes to be in the lipid raft environment?

A

certain transmembrane receptors - properties of the raft seem important in the modulation of the activity of these receptors

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53
Q

what do lipid rafts have to do with Alzheimer’s Disease?

A

play role in the pattern of cleavage in amyloid proteins
amyloid beta-peptide (Abeta) is derived from cleavage of a larger protein - major contributor to amyloid plaques that kill neurons. Cholesterol levels are important for Abeta formation. the epsilon4 allele of the apoE gene (carrier that delivers cholesterol within the CNS) is major risk factor for alzheimers - genetic evidence links cholesterol level to alzheimers

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54
Q

what do many of the functions of the membrane involve?

A

proteins that actually perform that function

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55
Q

what is an example of a membrane function that doesn’t require protein?

A

myelin membrane - insulate electrical signals passed by axons - protein content of myelin is less than 25% of membrane

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56
Q

what is an example of a function that requires lots of proteins?

A

production of ATP in mitochondrial membrane - protein content of internal mitochondrial membrane is approx 75% (just enough phospholipids to hold the thing together as a membrane)

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57
Q

what is the protein content of a typical plasma membrane?

A

approx 50% protein

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58
Q

what are the 8 ways proteins associate with the membrane?

A
  1. single transmembrane alpha helix
  2. multiple alpha helices span the membrane
  3. rolled up beta sheet (beta barrel) spans the membrane
  4. alpha helix only spans one leaflet of the membrane
  5. lipid is covalently attached to the protein & inserts into the inner leaflet
  6. membrane associated protein interacts via non-covalent binding to an oligosaccharide
  7. intracellular membrane associated protein interacts w/an integral membrane protein
  8. extracellular membrane associated protein interacts w/an integral membrane protein
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59
Q

What are characteristics of a membrane spanning alpha helix protein?

A

amino acids of protein are in lipid env.
Most must be uncharged for it to be energetically favorable
peptide bonds are polar, so they have to form H-bonds
alpha helix maxes h-bonds so outer surface is uncharged to interact w/hydrophobic tails

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60
Q

How does information transfer using a membrane spanning alpha helix?

A

ligand bonds to outside, helix can’t change much due to h-bonds, but can rotate, twist or move up & down - enough to create the signal that moves from outside to inside

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61
Q

What is a tight junction?

A
  • created by membrane proteins to create a diffusion barrier
  • i.e. epithelial cells w/apical membrane that has tight junctions b/t cells so that proteins can’t diffuse past the tight junctions
  • separates the membranes into domains
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62
Q

what do tight junctions do?

A

limit movement of proteins - creates domains in the membrane

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63
Q

What determines where membrane proteins go?

A

endoplasmic reticulum - sorts the membrane proteins & sends them to their destinations

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64
Q

do cells in tissues have sides?

A

yes, apical and basal

basal side faces the basement membrane,

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65
Q

what happens in retinal pigment epithelia?

A

have tight junctions: apical side involved in recycling components - absorbs nutrients from blood on basal side - drugs can be developed to target specific tissue regions by taking advantage of differences b/t apical and basal sides

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66
Q

What are some ways the mobility of proteins can be restricted?

A
  1. self-assembly into aggregates
  2. tethering by an extracellular protein (i.e. t-cells and b-cells get tethered by antigens)
  3. tethering by an intracellular protein
  4. cell-cell interactions (i.e. t-cells & antigen presenting cells)
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67
Q

Why is protein mobility restricted?

A

to achieve a purpose
often to construct a multi protein complex to perform a physiological task - like having many receptors signal together in one spot on the cell

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68
Q

where are protein lattices?

A

both inside & outside cells
intracellular lattice is cytoskeleton
intercellular lattice is basement membrane or extracellular matrix

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69
Q

what are cell membranes connected to?

A

w/in the cell - cytoskeleton

w/out the cell - extracellular matrix

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70
Q

what are the types of signaling?

A

direct cell-cell signaling
endocrine signaling - national news
paracrine signaling - neighborhood gossip
autocrine signaling - leaving yourself a note

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71
Q

what are some examples of cell to cell signaling?

A

immune system, integrins, cadherins

specificity is that cells have to be next to each other.

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72
Q

what are examples of endocrine signaling?

A

hormones - signal goes everywhere but only certain cells have receptors to receive the signal
specificity is the receptor

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73
Q

What are some examples of paracrine signaling?

A

eicosanoids, neurotransmitters, prostaglandins, leukotrienes
sometimes there’s a barrier to keep them local, many are proteins (enzymes) that are chemically unstable & can diffuse just a small ways before breaking down

74
Q

What is an example of autocrine signaling?

A

T-cell that is recognizing an antigen - has to stimulate itself to rapidly divide
cancer cells

75
Q

How do immune cells signal?

A

B-cells, T-cells & macrophages - highly mobile, express molecules on their cell surfaces - go places and do things - cell to cell interactions

76
Q

How do tissues use cell-cell signaling?

A

Interact w/mobile cells like immune cells & new blood vessels - interact w/each other through integrins & other cell adhesion molecules (involved w/keeping tissue together & also w/cell signaling).

77
Q

Where does specificity occur w/endocrine signaling?

A

at receptor level
cells w/out receptors ignore signal
signal distributed throughout body - perfect way to coordinate distant body parts towards one function

78
Q

where does the regulation occur with endocrine signaling?

A

at the point of release & at the point point of signal detection (cell could be turned on or turned off - used for a variety of purposes)

79
Q

Where is endocrine signaling used?

A

many different tissues for many different purposes - i.e. steroid hormones, insulin, and adrenaline

80
Q

Why does the body use paracrine signaling?

A

To keep a signal more or less localized.
regulation is at level of generating the signal. If molecule is unstable, it will only diffuse a few cell diameters b4 it degrades

81
Q

What tissues use paracrine signaling and for what purposes?

A

many different tissues, many different purposes. for example, NO is secreted by vascular endothelial cells & acts on vascular smooth muscle to promote relaxation

82
Q

What is synaptic transmission?

A

specialized form of paracrine signaling. concentration of neurotransmitter is high w/little or no leakage. diffusion from presynaptic terminal to postsynaptic receptor is super fast. allows neighboring cells to carry completely different signaling info. neurotransmitters are held in synaptic vesicles before they go across the synapse to the ligand-gated channels on the receiving side

83
Q

what is a synapse?

A

specialized structure where a tiny bit of fluid separates the presynaptic cell from the post synaptic cell

84
Q

What does autocrine signaling do?

A

provides a positive feedback loop, useful for rapidly promoting proliferation, immune response arises from activation of a single t-cell, cancer cells also make sure of this process for rapid division.

85
Q

How are blood sugar levels sensed?

A

in the beta cells of the islets of langerhans w/in pancreas

86
Q

What causes the release of insulin into the blood stream?

A

glucose sensors in the beta cells of islets of langerhans in pancreas sense glucose levels. [as an aside: pre-proinsulin is converted to insulin in vesicles derived from the Golgi]. when glucose levels rise, induces transient Ca++ release, promotes fusion of vesicles w/surface of beta cell & release of contents (insulin).

87
Q

What causes release of Histamine?

A

Histamine is released from Mast cells in response to allergens. Allergens bind to IgE expressed on surface of Mast cell. Binding induces signal transduction cascade that mobilizes Ca++ - promoste vesicular fusion & releases histamine.

88
Q

What is TNFalpha

A

tumor necrosis factor - important inflammatory signaling protein

89
Q

How is TNFalpha released from cell?

A

TACE (also a membrane bound protein) is a protease that cleaves TNFalpha (a membrane bound protein and a cytokine) (NOT a quantal release mechanism). Soluble TNF can diffuse to site of action. Soluble AND membrane TNF can activate TNFalpha receptors on neighboring cells.

90
Q

what is a protease

A

enzyme that breaks down proteins and peptides

91
Q

What happens to the remnant membrane TNF after getting cleaved?

A

it is recycled

92
Q

What is the point of a drug that can distinguish b/t soluble and membrane bound forms of TNF?

A

may have fewer side effects

93
Q

What kind of therapy might blockade of TNF signaling be used for?

A

treatment of rheumatoid arthritis

94
Q

What is continuous release?

A

signaling molecules that are released as soon as they are made

95
Q

what are some examples of continuous release molecules?

A

steroid hormones (estrogen, progesterone, testosterone, corticosterone, aldosterone), prostaglandins, cytokines (other than TNFalpha)

96
Q

Where is regulation with continuous release molecules?

A

at the level of synthesis of the signaling molecule (NOT at the level of release)

97
Q

how might synthesis regulation occur for continuous release signaling molecules?

A

could be transcriptional (synthesis of mRNA) or translational (synthesis of protein)

98
Q

how are continuous release molecules actually released?

A

peptides are released via a continuous vesicular exocytosis and small (uncharged) molecules diffuse out of the cell

99
Q

what is the benefit of diffusion for signaling molecule transport?

A

allows all cells w/in an area to receive the signal. if signal is also unstable & short-lived, this is a good mechanism to keep the signal localized - a strategy for maintaining specificity

100
Q

prostaglandins are an example of what?

A

signaling molecules that provide local signaling - many spontaneously degrade w/in minutes, some actively degraded by enzymes in lung

  • heavily used during inflammation
  • used by several organs to regulate blood flow (heart & kidneys)
  • used in brain to regulate fever
  • also many more processes
101
Q

What is a benefit of local signaling?

A

allows one molecule to be used for many different physiological purposes (like prostaglandin)

102
Q

What allows creation of concentration gradients?

A

diffusion

103
Q

what are concentration gradients often used for?

A

often during development to create specialized cells w/in a tissue - more signal leads to a fundamentally different cell response (different genes are activated) - multiple cell types within one tissue
-also create a direction

104
Q

Of what use is gradient created direction?

A

-immune cells follow gradients of signal to find infection
-more signals on one side of cell cause cell to extend its cytoskeleton in that direction while retracting cytoskeleton on all other sides
-result is net movement towards the source of the signal
also used in angiogenesis

105
Q

Receptor

A

a specific protein in either the plasma membrane or interior of a target cell with which a chemical messenger combines to exert its effects

106
Q

Down-regulation

A

a decrease in the total number of target cell receptors for a given messenger in response to chronic high extracellular concentration of the messenger

107
Q

Up-regulation

A

an increase in the total number of target cell receptors for a given messenger in response to chronic low extracellular concentration of the messenger

108
Q

Ligand

A

a compound (small molecule or protein) which binds to a receptor. A ligand can be an endogenous compound or a drug

109
Q

Affinity

A

The strength with which a chemical messenger binds to its receptor

110
Q

Agonist

A

a chemical messenger that binds to a receptor and triggers the cell’s response; often refers to a drug that mimics an endogenous messenger’s action. (activates)

111
Q

Antagonist

A

a molecule that competes for a receptor with an endogenous chemical messenger. The antagonist binds to the receptor but does not trigger the cell’s response (inhibits)

112
Q

Saturation

A

the degree to which receptors are occupied by a messenger. If all are occupied, the receptors are fully saturated; if half are occupied, saturation is 50%; etc.

113
Q

Specificity

A

Selectivity; the ability of a receptor to react with a limited number of structurally related types of molecules

114
Q

Competition

A

The ability of different molecules very similar in structure to combine with the same receptor

115
Q

Receptor binding vs. cellular effect

A

-effect of a signal on cell is not binary - # of receptors activated can correlate w/strength of cellular effect

116
Q

what is spare receptor theory

A

a maximal signal can often be elicited when only a small fraction of receptors are activated

117
Q

desenitization

A

loss of receptor sensitivity

118
Q

priming

A

increased receptor sensitivity

119
Q

how can receptor strength be modulated?

A

w/many important receptor systems - cell has ability to either increase the signal strength or decrease the signal strength caused by the occupancy & activation of a receptor

120
Q

what is an intracellular receptor?

A

lives inside the cell. ligand has to find a way into the cell by itself.

121
Q

what is an example of an intracellular receptor?

A

steroid hormone receptors:

examples of steroid hormones: glucocorticoids, mineralocordicoids, estrogens - diffuse across the cell membrane

122
Q

What happens when steroid hormone diffuses across the cell membrane?

A

binds to steroid hormone receptor to create receptor complex (activates the receptor), that binds to DNA & activates the transcription of new genes or blocks transcription of genes

123
Q

What is an example of an ion channel?

A

acetylcholine receptors

124
Q

how does the ACh receptor work?

A

It’s an ion channel. ACh binds to it and drives it to the open state. Continued binding of ACh drives receptor into desensitized state (closed), removal of ACh allows receptor to resume resting state. ACh is degraded by cholinesterases.

125
Q

What is the path to activation in the ACh receptor?

A

made up of lots of alpha helices - rotate & move in specific ways through the membrane to open the gate. Ion channel opens when you go from resting to activated/excited state so ions move through. quickly goes to desensitized state & stuck there until ACh is removed. then goes to resting state

126
Q

what places in your body use nicotinic acetylcholine receptors?

A

muscles and brain

so if you make ACh that can’t be degraded, you have a poison - patient is paralyzed

127
Q

How does calcium flood the pancreatic beta cell?

A

Glucose comes in the glucose sensor, goes through the citric acid cycle and metabolized to ATP. Another ion channel has binding site for ATP on the inside of the cell membrane. ATP binds & causes ion channel to close (it’s a K+ channel). loss of inward K+ current results in net depolarization of membrane. Voltage sensitive Ca++ channels open & bring Ca++ into the cell. Ca++ promotes vesicle fusion.

128
Q

How do sulfonylurea drugs work?

A

Target ATP sensitive K+ channels - keep them closed so more insulin is secreted (because voltage sensitive Ca++ channels open in response to depolarization, Ca++ promotes vesicle fusion). One of first drugs given to diabetes patients - induces insulin release by mimicking ATP in pancreatic beta cell.

129
Q

What are gap junctions?

A

6 membered protein structures (6 connexin molecules forming a hexagonal structure) that span a gap b/t adjacent cells & couple the cytoplasm of both cells
found in the heart & liver

130
Q

how do gap junctions form?

A

2 channels have to line up from 2 neighboring cells for a functional connection to be made - only then is a gap junction formed

131
Q

How is the opening & closing of gap junctions regulated?

A
  • low intracellular calcium opens the channel
  • high calcium closes the channel
  • calcium is the ligand and the gap junction is the receptor
  • purpose of closing gap junction is to protect the cell (increase in Ca++ is indicative of cellular damage)
132
Q

What can pass through a gap junction?

A

only ions & metabolites (it’s a small pore)

133
Q

How is the gap junction used by the body?

A
  • electrical coupling: heart & smooth muscle can react quickly to changes in electrical stimulation by contracting due to movement of ions through gap junction
  • metabolic signaling: liver produces glucose from amino acids when needed (gluneogdnesis). Adrenaline/epinephrine is secreted from nerve terminals to signal this event. As not all liver cells are next to nerve terminals, the signal is propagated through gap junctions to rapidly increase the liver’s response to maintain glucose homeostasis
134
Q

What good is gap junction inhibition?

A

maybe -
gap junctions are source of drug induced liver injury b/c intracellular inflammatory signaling molecules can be spread quickly through tissues via gap junctions
drug induced injury is one of most common reasons drug development is abandoned (tylenol is big offender)
-Patel & colleagues recently shown direct connection b/t gap junctions and drug induced liver injury - mice genetically engineered to be missing a liver gap junction gene are resistant to liver injury - identified a small molecule inhibitor of liver gap junctions & showed it protected against APAP induced liver injury.

135
Q

what is the structure of all g protein coupled receptors?

A

all have 7 transmembrane domain (serpentine receptor)

136
Q

How does ligand bonding affect g protein coupled receptors

A

ligand makes hydrogen bonds w/amino acids found on the outside of cell. # & strength of H-bonds determines affinity of ligand for its receptor. position of H-bonding amino acids determines the specificity of the receptor - only some ligands can interact
binding causes relatively stiff alpha helices to slide & rotate against each other
large effect on conformation of intracellular side of the receptor

137
Q

What happens when g protein coupled receptors get activated?

A

hormone binds to the receptors. There is a shape change. G protein which associates w/receptor when its inactive, releases from receptor (after it is activated) and migrates along membrane to interact w/its target. target is usually an enzyme, depending on the G protein it will either be turned on or turned off.

138
Q

why is a g protein called a g protein?

A

b/ it binds to GTP

139
Q

How do tyrosine kinase linked receptors work?

A

activation via dimerization of subunits:
go from 2 subunits w/single alpha helices (contain a kinase activity - puts phosphate covalently onto something), as monomer, kinase has no access to substrates, substrate for each kinase is the other subunit, ligand binds to both so they come together & supply each other with their substrates
phosphorylation alters the charge & so the conformation of the intracellular surface changes, creating a new binding site which recruits further signaling components. ta da!

140
Q

what are the physiological functions of the beta adrenergic receptor?

A
  • increase heart rate
  • increase blood pressure
  • decrease airway resistance
  • increase gluconeogenesis
  • increase muscle glycogen breakdown
  • fight or flight response
141
Q

How does the beta adrenergic receptor work?

A

It’s a G protein coupled receptor:
G protein is in 3 parts (alpha, beta gamma). before ligand binds to receptor, g protein has GDP bound to the alpha subunit. hormone(norepinephrine) binds to the beta adrenergic receptor, induces conformational change, GDP has lower affinity for binding site, GTP has higher affinity for binding site so kicks out GDP, bound GTP diffuses across membrane & finds adenylyl cyclic and cranks out cAMP.
g protein is an enzyme, but only involved in on-off signal, not the signal itself

142
Q

what health issues can be addressed by manipulating the beta adrenergic receptor pathway?

A

Heart disease - blocking receptors will decrease blood pressure
Asthma - activating receptors will open the airway (decrease airway resistance)

143
Q

What does g protein do when it’s activated?

A

shuttles to adenylate cyclase & activates enzyme (on switch)

144
Q

What happens to active G protein eventually?

A

bound GTP is hydrolyzed to GDP & alpha subunit returns to inactive receptor complex

145
Q

How does the enzymatic activity of the G protein affect its signal?

A

The more active the enzymatic activity of the G protein is, the faster the receptor’s signal turns off. Decreased GTPase activity results in a STRONGER signal

146
Q

What do g proteins do?

A

hydrolyze GTP to GDP

so when GTP is hydrolyzed to GDP, it then binds on the adrenergic receptor and turns off receptor’s signal.

147
Q

what do phosphodiesterases do?

A

supply the off signal by converting cAMP to AMP

148
Q

How can you increase levels of cAMP?

A

receptor mediated activation of adenylate cyclase levels

149
Q

How are adenylate cyclase & phophodiesterase activity regulated?

A

signal transduction events

150
Q

what does cAMP do?

A

binds to the regulatory subunits of PKA (protein kinase A)

151
Q

what is the structure of inactive PKA?

A

2 regulatory subunits (each w/2 with empty cAMP sites) and 2 catalytic subunits. substrate-binding sites on catalytic subunits are blocked by auto inhibitory domains of R subunits

152
Q

what happens when cAMP binds to PKA?

A

binds to regulatory subunits, catalytic subunits fall off & expose substrate binding sites - go off and do their thing -> removal of inhibition (common theme in signal transduction)

153
Q

what does PKA do?

A

phosphorylates numerous cellular proteins @ serine & threonine residues

154
Q

what does phosphorylation accomplish?

A
  • leads to activation or inhibition of downstream proteins
  • leads to cell specific responses
  • range of effects include ion channels, transport systems, secretion, metabolism & gene expression
155
Q

What is an important component of signal transduction?

A

signal amplification

156
Q

Where does signal amplification take place in signal transduction?

A

between active adenylate cyclase & cAMP, between active protein kinase & phosphorylated enzyme, and between phosphorylated enzyme and products
NOT between messenger-receptor and active adenylate cyclase or b/t cAMP and active protein kinase
activation occurs when we have enzymes

157
Q

what is the receptor/g protein linkage that stimulates glycogen breakdown and smooth muscle relaxation?

A

epinephrine is stimulus

beta2 adrenergic receptor, Gs protein, adenylate cyclase effector

158
Q

what is the receptor/g protein linkage that stimulates smooth muscle relaxation?

A

PGE2 is stimulus (prostaglandin), EP2 is receptor, Gs is G protein, Adenylate cyclase is effector

159
Q

what is the receptor/g protein linkage that stimulates vascular smooth muscle contraction?

A

norepinephrine is stimulus, alpha 1-adrenergic is the receptor, Gq is the g-protein, phospholipase C is the effector

160
Q

what is the receptor/g protein linkage that stimulates airway smooth muscle contraction?

A

LTC4 is stimulus, LTC4 receptor is the receptor, Gq is the g protein, phospholipase C is the effector

161
Q

What is the receptor/g protein linkage that slows pacemaker activity in the heart?

A

Acetylcholine stimulus, muscarinic m2AChR receptor, Gi-bg is g protein (i for inhibitor), K+ channel is the effector

162
Q

what is the receptor/g protein linkage that works on olfaction?

A

odorants are stimulus, olfactory receptor, G-olf protein, adenylate cyclase is effector

163
Q

what is the receptor/g protein linkage that works for visual excitation?

A

light is stimulus, rhodopsin is receptor, transducer is the g-protein, cGMP phosphodiesterase is the effector

164
Q

what is the physiological function of the muscarinic acetylcholine receptor?

A

feed or breed response:

  • decreased heart rate & blood pressure
  • increased blood flow to gut
  • decreased muscle glycogen breakdown and gluconeogenesis
165
Q

what kinds of things to g proteins do in muscarinic acetylcholine receptors (mAchR)?

A

some g proteins bind to ion channels (-potassium channels: (M current, GIRK channels, -voltage-operated Ca++ channels), some g proteins activate other kinases (MAP kinases, PKC) some g proteins inhibit adenylate cyclase

166
Q

what do muscarinic receptors do to blood pressure?

A

decrease it via NO (nitric oxide)

167
Q

How is nitric oxide made in the body?

A

by deamination of arginine via the enzyme NO synthase
NO synthase is activated via G protein coupled event
NO exists as gas dissolved in liquid environment. has very short half-life of 5-10 seconds - just enough time to diffuse to neighboring cell.

168
Q

how do muscarinic receptors activate NO synthase?

A

receptors of autonomic nervous system
NO rapidly diffuses across to smooth muscle cell
w/in cell, NO binds to its receptor, guanylyl cyclase
gynylyl cyclase converts GTP to cGMP (similar to production of cAMP), promotes relaxation of smooth muscle cell
-nitroglycerine relieves angina by being converted to NO

169
Q

What are some processes that are regulated by calcium binding?

A

muscle contraction (actin:myosin interactions)
cytoskeletal movement
vesicular fusion with the membrane
modulation of kinase activity

170
Q

what is the most important calcium binding protein?

A

calmodulin
makes up 1% of ALL proteins in the cell
many chemical signaling events modulated by calcium occur through interactions w/specific proteins

171
Q

what is CaM

A

calmodulin
consists of 1 polypeptide chain w/4 binding sites for calcium
at least 2 calcium ions must bind before CaM becomes active
when activated - marked conformational change
acts as translator for calcium events
extended when Ca++ isn’t present
number of signals regulated by calcium are enormous

172
Q

What is CaM kinase II?

A

calcium calmodulin kinase II
expressed at high levels in certain synapses
functions as molecular memory switch
when calcium is present, becomes activated
remains active even after calcium signal has decayed by self phosphorylation
ultimately, kinase is turned off by physically removing the phosphates w/a phosphatase
this is an example of using a transient signal to create a long lasting change - a memory event

173
Q

What is an example of a receptor tyrosine kinase?

A

the EGF receptor (epidermal growth factor receptor)

174
Q

how does the EGF receptor work?

A
  1. EGF binds to receptor & activates kinase activity w/in its intracellular domains
  2. kinase domains phosphorylate each other
  3. Grb-2/Sos complex recognizes the phosphorylated domain of the EGFR as a binding site & binds (Grb-2/Sos is protein complex)
  4. Sos binds to Ras. Ras is held @ surface of plasma membrane by fatty acid chain (farnesyl group) that inserts into the membrane. binding of Sos causes Ras to release a molecule of GDP & bind a molecule of GTP (ras like G protein)
  5. activated Ras (GTP bound) activates serene kinase called Raf-1, Raf-1 phosphorylates Mek-1 & activates it, Mek-1 phosphorylates Map kinase and activates it.
  6. Map kinase is released to perform multiple functions w/in the cell
    the more active the GTPAse, the less strong the signal
175
Q

What about Ras?

A

functions like a g protein, but different structure & doesn’t bind to serpentine receptors - all members of the Ras family are tethered to the membrane w/covalently attached lipid group.

176
Q

what does Ras do?

A

lots of things
insulin signaling
involved in process of proliferation: blockage of ras blocks cell proliferation in vitro while activation of ras promotes proliferation
30% of human cancers have activating ras mutations

177
Q

how has ras been targeted by drugs?

A

inhibiting transfer of the lipid (farnesyl group) onto the protein - called farnesyl transferase inhibitors - Ras is still functional but not localized to the membrane

178
Q

What is the MAPK signaling cascade?

A

combination of 3 kinases (evolutionarily conserved motif in signal transduction)
Ras GTPase is the input - activates MAPKKK which phosphorylates MPKK which phosphorylates MAPK (the output), MAPK can phosphorylate many targets w/in cell
one receptor activates many MAPK molecules (amplification)

179
Q

why is the 3 kinase cascade useful?

A

several different MAPKKK, MAPKK & MAPK proteins - many can interact to form different cascades & exist w/in the same cell, so dozens of proteins can form hundreds of different & unique cascades
specificity is maintained by preassembling these units
so you can combine different inputs & outputs using an adaptor (middle) kinase

180
Q

What are examples of duration of signal using MAP kinase cascade?

A

EGF mediated Ras activation peaks at 5 minutes then declines

Nerve growth factor (NGF) mediated Ras activation remains high for hours - cell leaves the cell cycle & differentiates

Mechanism of Disease (4 decks)

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