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WEEK 2 Flashcards

1
Q

describe neurotransmitters

A

rely on diffusion
made and released from neurons
used for rapid communication over short distances
effects are short lived

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2
Q

describe hormones

A

made and released from endocrine cells
act over long distances
take a long time to act and effects are long lasting

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3
Q

describe drugs

A

exogenous substances
used to mimic (agonist), increase or block (antagonist) effects of first messengers

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4
Q

name the interactions that occur in receptor-ligand interactions

A
  • hydrophobic force
  • van der Waals
  • hydrogen bonding
  • electrostatic interactions
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5
Q

what does it mean when Kd is high

A

the dissociation constant is high when the receptor and ligand have a low affinity for each other

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6
Q

what does it mean when Ka is high

A

the association constant is high when the receptor and ligand have a high affinity for each other

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7
Q

Ka (or Kf) equation

A

[RL] / [R] *[L]

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8
Q

what is pharmacokinetics

A

the study of the time course of drug absorption, distribution, metabolism and excretion

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9
Q

what is pharmacodynamics

A

the relationship between drug concentration at the site of action and the resulting effect

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10
Q

what is the relationship between EC50 and drug potency?

A

the lower the EC50 the more potent the drug.
meaning less of the drug is required to produce a meaningful effect

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11
Q

what do agonists do?

A

mimic the effect of the endogenous ligand’s activation of its receptor to produce a response

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12
Q

what do partial agonists do?

A

partial agonists bind and activate a receptor but do not elicit a full response

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13
Q

what do superagonists do? what is their relative efficacy?

A

they show a higher efficacy than full agonists. their efficacy is at 200%

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14
Q

what do antagonists do?

A

they bind to the endogenous ligand’s receptor and block the signal molecule from producing a biological response.

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15
Q

what do inverse agonists do?

A

they bind to the endogenous receptor and exert the opposite biological response.

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16
Q

examples of non-chemical signals

A

mechanical forces, light, temperature

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17
Q

receptors can be on the _____ and in the _____

A

cell surface ; intracellular space

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18
Q

what are the types of cell surface receptors

A

ligand gated ion channels
GPCR
Catalytic receptors
- Guanylyl cyclase, RTKs, extrinsic protein tyrosine kinase, RTSKs, and Receptor tyrosine phosphatase

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19
Q

types of intracellular receptors

A

nuclear and cytoplasmic

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20
Q

describe ligand gated ion channels

A
  • aka ionotropic
  • binding domain for a specific ligand is at the extracellular domain of the receptor
  • binding event opens the ion channel
  • two states are open and closed
  • regulate ion flow across the plasma
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21
Q

describe G-protein coupled receptors

A
  • aka metabotropic
  • diverse signals and effects
  • extracellular ligand binding domain
  • intracellular binding domain for a G protein
  • Seven transmembrane spanning domains
  • No pore
  • signal transducer by GTP binding proteins known as G proteins
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22
Q

how do catalytic receptors signal

A

through intrinsic enzyme activity or closely associated enzyme activity

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23
Q

describe catalytic receptors

A
  • have an extracellular binding domain
  • a single membrane spanning domain
  • a catalytic domain
  • endogenous agonists = diverse peptides and proteins
  • ligand binding triggers dimerization
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24
Q

Guanylyl cyclase is also known as a

A

natriuretic peptide receptor

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25
Q

describe atrial natriuretic hormone

A
  • ANP
  • secreated from atrial myocytes
  • synthesized by magnocellular neurons of the brain
  • receptors are dimers
  • activation increases guanylyl cyclase activity
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26
Q

largest subclasses of catalytic receptors are____ . Describe it.

A
  • Receptor tyrosine kinases (RTKs)
  • respond to diverse ligands (EGF, insulin, VEGF, etc. )
  • play important roles in cell growth, differentiation, cell survival, and metabolism
  • mutations in RTKs and aberrant activation of their intracellular signaling pathways have been linked to many diseases and cancers
  • important targets for therapeutic effects
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27
Q

what is the mechanism of RTK activation

A
  • when ligand binds to RTK, neighboring RTK dimerize
  • dimerization activates the tyrosine kinase activity in RTKs through phosphorylation (autophosphorylation or cross-phosphorylation)
  • phosphorylated receptor now serves as a site for activation and assembly of intracellular signaling proteins
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28
Q

Activated RTKs serve as docking sites for intracellular signaling proteins that contain _____ and attract ______

A

SRC homology 2 (SH2)
phosphotryosine binding (PTB) ;

intracellular signaling proteins and docking proteins

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29
Q

describe Ras in the Ras-MAPK pathway

A
  • small, monomeric G protein
  • anchored to the inner leaflet by covalent bound to lipid
  • it’s activation is regulated by Guanine exchange and hydrolysis through GEF and GAP proteins
  • its activation requires adaptor proteins called Grb2 and Sos
  • Ras swaps GDP for GTP
  • it’s activation, activates several downstream targets
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30
Q

What kind of domain does Grb2 in the Ras-MAPK pathway have

A

an SH2 domain

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31
Q

Sos in Ras-MAPK pathway is what type of protein?

A

GEF protein

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32
Q

Sos binds ____

A

Grb2 and Ras

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33
Q

what targets are activated by Ras activation

A

Raf kinase (activated by Ras)
MEK (activated by Raf-P)
MAP kinase (activated by MEK-P) and ERK

*SEE SLIDE 25

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34
Q

Why is MAP Kinase important in the Ras-MAPK pathway

A
  • phosphorylated MAP kinase is a transcription factor that upregulated proteins important for cell proliferation
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35
Q

Ras hyperactivation is associated with what disease

A

cancer

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36
Q

Name an example of when the Ras-MAPK pathway is used

A

epidermal growth factor
cell migration and adhesion

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37
Q

JAK-STAT is what type of catalytic receptor

A

extrinsic protein tyrosine kinase

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38
Q

what is the use of JAK-STAT in the body

A

-hematopoiesis (formation of blood cellular components)
- tissue repair
- inflammation
- apoptosis

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39
Q

describe Janus Kinase (JAK)

A
  • non-covalently associated with cytokine receptors
  • doesn’t bind to the receptor until the receptor is activated by the ligand
  • JAK autophosphorylates and adds phosphates to receptor
  • recruits STAT
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40
Q

describe Signal transducer and activator of transcription (STAT)

A
  • STAT binds to the phosphorylated tyrosine on the receptor
  • once bound they leave and take the phosphate with it to dimerize with the other STAT
  • JAK-STAT process continues as long as ligand is bound to the receptor
  • this is the most rapid activation of transcription factors
  • loss or mutation of JAK/STAT components is related to many human diseases
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41
Q

intracellular receptors can only interact with ligands that can _____ the plasma membrane

A

cross

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42
Q

what type of ligands interact with intracellular receptors

A
  • lipophilic vitamins
  • steroid hormones
  • nitric oxide
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43
Q

Inactive intracellular receptors are bound to _____

A

heat shock protein 90

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44
Q

what are the three steps of signal transduction

A
  1. receive first messenger
  2. signal transduction
  3. response
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45
Q
  1. signals that effect cytoskeleton proteins produce what kind of effect
  2. signals that effect gene regulatory proteins produce what kind of effect
  3. signals that effect metabolic regulatory proteins produce what kind of effect
A
  1. altered cell shape or movement
  2. altered gene expression
  3. altered metabolism
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46
Q

who discovered second messengers, specifically cAMP

A

Earl sutherland & ted Rall

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47
Q

glycogen phosphorylase is the key enzyme in breaking down

A

glycogen. this reaction is called glycogenolysis

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48
Q

where does glycogen breakdown (or glycogenolysis) happen? and what is cleaved off from the glycogen polymer

A

in hepatocytes ; glucose 1-phosphate is cleaved from the polymer

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49
Q

types of second messengers include

A

hydrophobic molecules- cannot leave the membrane (DAG)

Hydrophilic molecules- can diffuse throughout the cytosol (cAMP, cGMP, IP3)

Ions (calcium)

Gases- can diffuse through aqueous and lipid settings (NO, CO)

Soluble proteins (JAK/STAT)

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50
Q

G-proteins are found in the genomes of _______

A

bacteria, yeast, plants, invertebrates, and all mammals

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51
Q

describe GPCRs

A
  • is a monomeric proteins.
  • a multi-pass transmembrane protein (7 spanning)
  • has an extracellular binding domain
  • the intracellular G-protein binding domain includes C3, C4, and sometimes C2
  • GPCR activation actives G-proteins
52
Q

G-proteins are ______ binding proteins and act as molecular switches

A

heterotrimeric guanine nucleotide

53
Q

describe the subunits of G-proteins

A
  • alpha subunit contains the nucleotide binding domain and has endogenous GTPase activity. (where GTP/GDP bind)
  • the alpha and gamma subunits are covalently anchored to the membrane
  • the beta and gamma subunits remain bound, alpha does not, and move as a unit
54
Q

describe “off” state of G-protein

A
  • attached to the GPCR at the inner membrane
  • GDP is attached to Ga
55
Q

describe ligand binding to GPCR

A
  • helps release of GDP from Ga
  • binds GTP; this causes conformational change that results in dissociation of Ga-GTP and GBy
56
Q

describe the timing mechanism

A

the intrinsic GTPase activity of the Ga subunit means that the G protein can only be active for a short period of time.
- GTP is hydrolyzed to GDP returning Ga to its inactive state which is Ga-GDP

57
Q

what happens when GBy reassociates with Ga-GDP

A

terminates all effector interactions

58
Q

describe PKA

A
  • major target of cAMP
  • PK-A is a heterotetramer: it has 2 regulatory subunits, and 2 catalytic subunits
  • catalytic subunits are phosphorylated by adding phosphate groups to serine and/or threonine residues
  • C subunit can also diffuse to the nucleus where it phosphorylates transcription factors.
59
Q

what happens when GPCR is coupled to Gai

A
  • Gai-GTP inhibits adenylyl cyclase
  • intracellular cAMP levels fall
  • no longer sufficient cAMP to bind subunits of PK-A
  • regulatory and catalytic subunits reassemble, inactivating PK-A
60
Q

intracellular cAMP levels can be regulated by cAMP phosphodiesterase (PDE). True or False

A

True. PDEs mediate termination of cAMP and cGMP

61
Q

what are the four major classes of second messengers

A
  • cyclic nucleotides
  • lipid messengers that signal w/in the cell membranes
  • ions that signal within and between cellular compartments
  • gases and free radicals
62
Q

what types of first messengers produce second messenger cAMP

A

Neurotransmitters (epinephrine, acetylcholine)
hormones (ACTH, CRH, Glucagon, LH)

63
Q

What is the signal transducer for cAMP

A

GPCR-Gs, GPCR-Gi

64
Q

what is the primary and secondary effector of cAMP

A

primary: adenylyl cyclase
secondary: PKA, cyclic nucleotide gated ion channels

65
Q

Viagra (Sildenafil citrate) is an example of

A

an cGMP PDE inhibitor. it increases cyclic nucleotides, specifically cGMP.
- it helps treat erectile dysfunction

66
Q

How is cAMP regulated

A
  • stimulating and inhibiting adenylyl cyclase
  • cAMP PDE
67
Q

PKA ______ cAMP phosphodiesterase

A

activates

68
Q

intracellular cAMP concentration levels regulate _____ activity

A

PKA

69
Q

active phosphoprotein phosphatase 1 (PP1) vs. inactive PP1? what inactivates PP1

A

active PP1 dephosphorylates activated proteins
inactive PP1 does not.

PP1 is inactivated by phosphoprotein phosphatase inhibitor (I-1)

70
Q

glycogen breakdown in skeletal muscle: what do the catalytic subunits of active PKA do?

A

once cAMP binds to PKA, activating it the catalytic subunits help:

  1. activate phosphorylase kinase (PK); this activates glycogen phosphorylase allowing for glycogen breakdown
  2. inactivates glycogen synthase; this inhibits the build up of glycogen
  3. inhibits PP1, by phosphorylating I-1 which binds to PP1
71
Q

How does the cholera toxin protein work

A
  • cholera passes through gastric acid barrier and colonizes the small intestine
  • the A subunit of Cholera Toxin (CT) bind to the G-protein causing ADP-ribosylation of arginine residues
  • Gs is locked in its active form
  • Na+/H+ exchanger (NHE) is blocked, prohibiting Na from entering
  • in addition to the build up of Na outside the cell, Cl-, HCO3-, and H2O remains on the outside
  • cells dehydrate
  • body dehydrates, diarrhea, death
72
Q

how does the Pertussis toxin (PTX) work (whooping cough)

A
  • the “A protomer” from PTX and NAD+ uncouples the Ga-inhibitory from the GPCR
  • this increase adenylyl cyclase activity.
  • cAMP levels rise and accumulate
  • cascade continues to be stimulated b/c of the high levels of intracellular cAMP
73
Q

cGMP has a ______ nucleobase, whereas cAMP has a ______ nucleobase.

A

guanine ; adenine

74
Q

cGMP is derived from _______ triphosphate

A

guanosine. (GTP)

75
Q

the two primary pathways for cGMP synthesis (hint: receptors)

A
  1. membrane bound guanylyl cyclase
    (this is a natriuretic peptide receptor; a subdivision of catalytic receptors)
  2. soluble guanylyl cyclase via Nitric Oxide activation
76
Q

How is cGMP degraded

A

cGMP PDEs:
- specific cGMP PDEs, such as PDE-5A
- non-specific PDEs, such as PDE-2 and PDE-3 which can degrade cAMP and cGMP

77
Q

PDE-5A is a _____

A

cGMP specific PDE

78
Q

PDE-2 and PDE-3 can hydrolyze

A

cGMP and cAMP (into GMP and AMP respectively)

79
Q

cGMP activates cGMP ion gated channels and which protein kinase?

A

Protein Kinase G

80
Q

PKG (protein kinase G) is expressed in which areas

A
  1. brain
  2. lungs,
  3. vascular tissue
81
Q

where are cGMP gated ion channels found in the body?

A

in photoreceptors which are important for phototransduction (eyes).

82
Q

histamine is ligand that can activate _____

A

phospholipase A2

83
Q

Phospholipase A2 hydrolyzes ________ to produce Arachidonic acid

A

membrane phospholipids

84
Q

Arachidonic acid is a precursor to which pathways

A

cyclooxygenase pathway and lipoxygenase pathway

85
Q

the cyclooxygenase pathway can be blocked by what?

A

Aspirin and NSAIDs

86
Q

Why does aspirin have anti-inflammatory effects and anticoagulant effects

A

Aspirin blocks the cyclooxygenase pathway, inhibiting the production of prostaglandins which cause inflammation and vascular effects and thromboxanes which cause blood clotting and other vascular effects

87
Q

the Lipoxygenase pathway produces _____ which cause ________ and _______

A

Leukotriennes; allergic ; inflammatory reactions

88
Q

Phospholipase C-β is activated by ______

A

GPCRs

89
Q

Phospholipase C-γ is activated by ______

A

tyrosine kinase

90
Q

Name examples of phospholipase C-β hormonal ligands

A

Hormones: angiotensin, GnRH, GHRH, Oxytocin, TRH

91
Q

name the secondary messengers and effectors of phospholipase C-β

A

secondary messengers: IP3; DAG; Ca2+

Secondary effector: Protein kinase C and calmodulin

92
Q

IP3 stimulates the release of Ca2+ from ______

A

the SER (Smooth ER) and the Mitochondria

93
Q

DAG is a derived from _____ and stimulates _____

A

PIP2 ; PK-C (protein kinase C)

94
Q

PLC hydrolyzes PIP2 to produce DAG and IP3. True or False

A

True.

95
Q

DAG diffuses through the cytosol. True or false

A

False. DAG is a hydrophobic second messenger and therefore remains in the membrane while IP3 is hydrophobic and diffuses through the cytosol.

96
Q

what does the SERCA do in the Smooth ER

A

it pumps Ca2+ back into the SE.
- it is an anti-porter. it utilizes ATP to do this

97
Q

IP3 is bi-phasic. True or False

A

False. DAG is bi-phasic.

98
Q

Explain what the second wave of DAG comes from.

A
  • the slow DAG wave is caused by the breakdown of Phosphatidylcholine (PC) by PLCβ and PLD
  • the first wave is caused the DAG released from the hydrolysis of PIP2 by PLCβ
99
Q

What are Protein Kinase C functions (HINT: S.S.I.R.R L)

A

Smooth muscle contraction
Secretion
Immune responses
Receptor desensitization
Regulating transcription and Cell growth
Learning and memory

100
Q

name the three types of functional protein kinases C

A

conventional , novel, and atypical

101
Q

describe the main differences between conventional, novel, and atypical PKCs

A

conventional: are activated by Ca2+ and DAG

novel: only activated by DAG

atypical: not activated by either Ca2+ or DAG

102
Q

What is an extracellular and intracellular source of calcium?

A

extracellular: calcium from the ECF can be transported the ICF through calcium channels

intracellular: calcium stores in the SER and mitochondria can be released into the cytoplasm

103
Q

How can calcium be removed from the ICF

A
  • pumps: Ca-ATPase and Ca-Na exchangers can move calcium out of the cell or into the ER
104
Q

How can calcium concentration be buffered in the ICF

A
  • use of binding proteins such as parvalbumin and calbindin
105
Q

What is the glucose equivalent of 1 epinephrine molecule

A

10^8 Glucose 1-phosphate molecules

106
Q

What is an example of first messengers interacting with different receptors thus producing different responses in different cells

A

Acetylcholine (ACH):
1. binds ionotropic/nicotinic in skeletal muscle = muscle contraction

  1. binds metabotropic/GPCR in heart muscle = reduces rate and force of muscle contraction
107
Q

What is the name of a molecule that is small, highly diffusible, a non-protein organic molecules or ions that have very specific target proteins they regulate by altering their targets’ activity.

A

second messengers

108
Q

why are second messengers not rate limited? and what is their effect because of this

A
  • they are produced from abundant precursor molecules or rich intracellular stores
  • b/c they are not rate limited they can provide rapid and efficient signaling that is temporarily precise
109
Q

True or False:
1. compared to proteins, second messengers are tightly and rapidly controlled. True or False.

  1. Second messengers are not spatially controlled
A
  1. True
  2. False. Second messengers are spatially controlled
110
Q

Convergence vs. Divergence

A

Convergence - several different second messenger pathways can converge on a single target effector, producing an amplified effect.

divergence-
1. describe the different effects of a single first messenger on different cell types.
2. It can also be used to refer to diffusible intracellular second messengers that can also target different downstream effectors leading to a single first messenger having divergent effects.

111
Q

what is the time scale for diffusion and opening ion channels

A

10 um/1-10 seconds; milliseconds

112
Q

what is the time scale for Mammalian transcription?

A

10-100 nucleotides/sec or 10 min/gene

113
Q

what is the time scale for Mammalian translation?

A

10 amino acids/sec or 1 min/protein (300 aa)

114
Q

categorize mTOR in terms of kind of receptor

A

Catalytic receptor: RTSKs (receptor serine/threonine protein kinase)

115
Q

what is the catalytic subunit of mTOR complex 1 & 2

A

mTOR

116
Q

Fill in:

mTOR stands for ________________
mTOR is the major regulator of ____________
mTOR Controls ___________ processes
mTOR is a member of the __________ family

A
  • mammalian target of rapamycin
  • growth in animals
  • anabolic and catabolic
  • PI3K-related kinase (PIKK)
117
Q

True or False. mTOR Responds to nutrients and nutrient-induced signals

A

True. such as insulin

118
Q

What is the difference between mTOR1 & mTOR2 subunits

A

mTOR1 has subunits Raptor and PRAS40
mTOR2 has subunits mSin1 and Rictor

119
Q

compare mTOR1 and mTOR2

A

mTOR1:
- mTOR complex 1 promotes cell growth & proliferation
- Growth factors (insulin/insulin like), Energy status, Oxygen, Amino acids activate mTOR complex 1
- Inhibited by rapamycin

Promotes: protein synthesis, de novo lipid synthesis, synthesis of nucleotides needed for DNA replication and ribosome genesis, a shift away from oxidative phosphorylation to glycolysis, lysosome and mitochondria biogenesis

suppresses: protein catabolism (autophagy)

mTOR2:
- mTOR complex 2 controls cell survival, proliferation and regulates cell growth
- signals primarily come through insulin/PI3K signaling

Regulates: Lipogenesis, Glucose metabolism, the actin cytoskeleton, and Apoptosis (cell death)

insensitive to rapamycin

120
Q

does fasting inhibit or activate mTOR1

A

inhibits

121
Q

At high nutrient levels mTOR1 ________ catabolism and ________ anabolism

A

inhibits catabolism and activates anabolism

122
Q

True or false. Dysregualtion of mTOR is associated with negative physiological outcomes

A

True.

123
Q

select the right answer.

mTOR effects are ______

A. gene-specific
B. ligand-specific
C. nutrients-specific
D. cell-specific

A

D. cell-specific

124
Q

When is mTORC1 activity optimal?

A

at caloric restriction

125
Q

explain chronic mTORC1inhibition and activation

A

advanced human physiology (13 decks)

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