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ZOOL 461 > Introduction and mechanisms endocrinology > Flashcards

Introduction and mechanisms endocrinology Flashcards

1
Q

Describe the derivation of the word “hormone”

A

The term hormone was introduced by Ernest Starling in 1905, derived from the Greek word meaning “to arouse or excite”

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2
Q

Describe how the nervous system and endocrine glands are interrelated

A

Sensory organs. (nervous system) receive information. Information is then sent to CNS. CNS integrates the info and coordinates a response (can be an endocrine response or trigger a target organ) in the appropriate location (metabolic, movement response, etc)

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3
Q

In general, the nervous system controls the ____ activities, while the endocrine system regulates the _____ functions

A

Rapid, slower

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4
Q

What’s the definition of a hormone?

A

Chemical messengers produced by one cell to regulate activity of another cell and delivered by means of endocrine, neuroendocrine, paracrine, autocrine, neurocrine, or pheromonal route.

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5
Q

Endocrine route (and give an example)

A

The hormone is released into the circulation and is transported to the target cell by blood vessels
- Ex: gonadotropin hormones secreted from pituitary -> target tissue (testis/ovary)

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6
Q

Neuroendocrine route (and give an example)

A

The hormone is released by nerve cells into the circulation and is transported to the target cells
- Ex: Vasopressin is secreted by hypothalamic neurons via pituitary -> target tissue kidney and vascular smooth muscle

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7
Q

Paracrine route (and give an example)

A

The hormone is released and diffuses to its target cell through the immediate extracellular fluid
- Secretory cells are close to target cells (doesn’t need to be secreted into circulation)
- Ex: Many growth factors such as epidermal growth factor-1

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8
Q

Autocrine route (and give an example)

A

The target of the secreted hormone is the same cell that released it
- Ex: Prostaglandins and some growth factors

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9
Q

Neurocrine route (neuronal communication) and give an example

A

Neurons secrete the hormone in the immediate vicinity of the target cell
- Ex: neurotransmitters such as norepinephrine and dopamine (some neurotransmitters are considered hormones)

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10
Q

Pheromone route (and give an example)
- May also be called something else

A

The hormone is released into the environment to induce a biological response in another animal. It is usually species specific and may also be called EXOCRINE ACTION.
- Ex: Reproductive pheromones in mammals, fish and insects. One specific example is the 17α,20β-P which is produced by female fish during ovulation and is secreted through urine to be detected by male fish.

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11
Q

True or false: Pheromones are species specific

A

True
- e.g. fish pheromones don’t target sharks

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12
Q

What 4 molecules are involved in information transfer (i.e. what are the four types of hormones?)

A
  1. Peptides and proteins
  2. Steroids
  3. Amino acids and amino acid derivatives
  4. Eicosanoids
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13
Q

Describe peptide and protein hormones and give some examples (3)

A
  • Can be short or long
  • Short example: TSH-releasing hormone, which is only 3 amino acids long
  • Medium example: Insulin, which is 51 amino acids long
  • Long example: growth hormone, which is 200 amino acids long
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14
Q

Describe steroid hormones and give 4 examples

A
  • lipid-soluble
  • derived from cholesterol
  • Ex: Androgens (e.g. testosterone), estrogens (female sex hormone), progestogens (version of progesterone), corticosteroids (adrenal steroids)
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15
Q

Give some examples of amino acid/amino acid derivative hormones

A

Thyroid hormones (iodithyronines, like thyroxine that forms from 2 tyrosines) and catecholamines (e.g. epinephrine)

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16
Q

Describe eicosanoids and give some examples

A

Hormones derived from arachidonic acids, which are released from phospholipids
- Ex: prostaglandins, prostacyclins

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17
Q

True or false: Ions are incapable of acting as chemical messengers

A

False, ions are capable of acting as chemical messengers

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18
Q

Describe hormone receptor interactions

A
  • Hormones interact with their target cells by binding to specific molecules termed receptors
  • Hormone specificity is achieved by a lock and key mechanism
  • Activation requires correct shape and charge of hormone
  • Binding of hormone to receptor is required but doesn’t necessarily cause receptor activation
  • Just because it fits in the lock, doesn’t mean it opens the door
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19
Q

True or false: a given receptor can bind a variety of hormones

A

False. Receptors are very specific to their hormones.

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20
Q

What are the two functions of hormone receptors?

A
  1. Recognition - specific binding
  2. Activation and transduction of signal
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21
Q

Agonists

A

Stimulate biological activity

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22
Q

Antagonists

A

Blocks biological activity
- A lot of drugs are antagonists

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23
Q

Competitive antagonists

A

Bind, but do not stimulate biological activity
- Occupies the binding pocket of the receptor so hormone is blocked from even binding

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24
Q

True or false: antagonists always bind the receptor binding site of the receptor

A

False
- Some antagonists have an allosteric effect, where they bind a site distant from the binding pocket and change the conformation of the receptor so that the hormone itself cannot bind

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25
Q

Hormone-receptor interaction is…

A

Rapid and reversible
- Dynamic process, hormone is constantly going through association and dissociation

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26
Q

K+1

A

Association rate constant
- H+R -> H-R
- represents how fast the hormone binds the receptor.

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27
Q

K+1 (association rate constant) units

A

M^-1 sec^-1
- Function of time

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28
Q

K-1

A

Dissociation rate constant
- H-R -> H + R
- represents how fast the hormone-receptor complex dissociates.

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29
Q

K-1 (dissociation rate constant) units

A

sec^-1

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30
Q

Ka formula

A

K+1/K-1

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31
Q

Ka units

A

M^-1

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32
Q

Ka represents what?

A

Equilibrium Association constant (Affinity)
- At equilibrium, for every one molecule of hormone that binds a receptor, another hormone dissociates from its receptor.
- It quantifies how readily the hormone binds to the receptor.
- A high Ka means the receptor has a high affinity for its receptor

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33
Q

Kd formula

A

1/Ka

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34
Q

Kd units

A

M

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35
Q

Kd represents what?

A

Equilibrium Dissociation Constant

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36
Q

Describe the % biological response on a dose-response relationship graph at a hormone concentration of 0 M

A

Basal response
- No hormone, but response is never 0 unless organism is dead

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37
Q

What is ED50 on a dose-response curve?

A

The effective dose giving half maximal hormonal response
- It is a measure of potency (effectiveness) and a function of receptor affinity

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38
Q

What is max response on a dose-response hormone curve?

A

Function of receptor density, aka # of receptors
- All receptors are occupied (saturated)

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39
Q

True or false: increasing [hormone] at max response on dose-response curve increases the % response

A

False; all the receptors are saturated at the max response so increasing [hormone] would have no effect

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40
Q

High Kd value means ____ affinity

A

Low

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41
Q

Low Kd value means ___ affinity

A

High

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42
Q

ED50 is analogous to…

A

Kd

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43
Q

At what concentration are hormones administered to patients at when [hormone] is low?

A

Near ED50
- Doses too low may not provide the desired therapeutic effect, while doses too high can lead to adverse effects.

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44
Q

______ and ______ are regulated by a variety of physiological and pharmacological factors

A

Receptor binding affinity and capacity are regulated by a variety of physiological and pharmacological factors

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45
Q

Capacity meaning in hormones

A

Maximum % response reached

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46
Q

Increased receptor synthesis and availability _____ receptor capacity

A

Upregulates

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47
Q

Decreased receptor synthesis and availability _____ receptor capacity

A

Downregulates

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48
Q

How does ED50 typically change?

A

ED50 change is usually due to changes to hormone and/or receptor conformation.
- Receptor number can change up and down, but this doesn’t change ED50
- Receptor affinity is also affected by covalent changes (e.g. phosphorylation)

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49
Q

On a dose-response curve, if the curve were to shift left but maintain the same max response, what happens to hormone affinity for receptor?

A

ED50/Kd would decrease, so affinity would be higher
- Need less hormone to reach max response

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50
Q

How do Kd and ED50 differ?

A

Kd is characteristic of a single receptor. ED50 is related to a biological response.

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51
Q

If a disease decreases hormone potency, what happens to the dose-response curve?

A

Curve shifts right (ED50 increases), capacity stays the same

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52
Q

If there’s a decrease in receptor synthesis, what happens to the dose-response curve of the hormone?

A

Capacity decreases, ED50 remains the same

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53
Q

Overall, change in receptor capacity affects…

A

Maximum responsiveness

54
Q

Overall, change in receptor affinity affects…

A

ED50

55
Q

What 2 categories do hormone receptors fall into?

A
  1. Intracellular receptors
  2. Plasma membrane receptors
56
Q

Describe intracellular receptors and give two examples of hormones with these receptors

A

The receptor molecule is inside the cell (in the cytoplasm or nucleus)
- Ligand has to actually pass through the cell to bind to the receptor because binding domain is inside the cell
- e.g. steroids and iodothyronines

57
Q

Describe plasma membrane receptors and give three examples of hormones with these receptors

A

The recognition sites lie at the cell surface
- Binding domain is on the outside of the cell
- e.g. peptide, protein and catecholamines

58
Q

Are membrane-associated receptors in the inside of the cell (e.g. in the ER membrane) considered plasma membrane receptors or intracellular receptors?

A

Plasma membrane receptors

59
Q

Some transcription factors are found in the cytoplasm as inactive, but are then activated upon binding a steroid hormone. The TF then translocates to the nucleus. What are these transcription factors considered?

A

Considered to be ligand-activated transcription factors.

60
Q

What is membrane fluidity determined by? 2 things

A
  1. The amount of cholesterol
  2. Fat saturation
61
Q

What does membrane fluidity allow for in terms of membrane receptors?

A

At physiological temperature, receptors in the bilayer are mobile. This allows interaction between receptors and other membrane proteins such as G-proteins, and receptor aggregation.

62
Q

What 2 things is required for the initiation of a biological response by a hormone?

A
  1. Specific binding (hormone-receptor specificity)
  2. Transduction of signal coupled to intracellular effectors
63
Q

Binding of a hormone to a receptor results in a _______ that activates the receptor

A

Conformation change

64
Q

Hormones that use intracellular receptors are hydrophobic. How do they travel through the circulation upon reaching a cell? How do they enter the cell?

A

Usually bound to carrier proteins in the blood that increases their half-lives.
- They dissociate from the binding protein and enter the cell through the cell membrane by diffusion (steroids) or facilitated transport (thyroid hormones).

65
Q

How do steroid hormones enter the cell?

A

Through diffusion

66
Q

How do iodothyronines enter the cell?

A

Through facilitated transport

67
Q

Intracellular receptors are _________ transcription factors, with each receptor containing which 3 domains?

A

Intracellular receptors are ligand-activated transcription factors, with each receptor containing hormone binding, DNA binding and activation domains.

68
Q

In most cases, there are suppressor proteins bound to DNA. What happens to these suppressors when ligand-activated transcription factors are activated?

A

Activation of receptor makes these proteins dissociate.

69
Q

Once the hormone-receptor complex (transcription factor) is activated, what does this complex interact with? What does this region activate?

A

The activated hormone-receptor complex interacts with a specific sequence of DNA referred to as a hormone response element (HRE).
- The HRE activates the promoter which leads to transcription.

70
Q

Summarize intracellular receptor activation, specifically for ligand-activated transcription factors (10 steps)

A
  1. Steroid hormone enters the cell
  2. Hormone binds specifically with nuclear receptor protein
  3. Activated hormone-receptor complex interacts with steroid response element (SRE) on the DNA
  4. Stimulation of the regulatory region of the DNA strand by the activation domain
  5. Stimulation of promoter region
  6. Activation of DNA-dependent RNA polymerase
  7. Initiation of transcription
  8. Production of new mRNA
  9. Translation of the message on ribosomes
  10. Production of new protein
71
Q

The receptor-effector coupling membrane receptors can be achieved by with which two ways?

A
  1. A process intrinsic to the receptor (i.e. receptor and effector are on the same molecule, receptor itself triggers a biological response)
  2. Through interaction of the receptor with other membrane proteins (like a G protein, for example)
72
Q

When the membrane receptor and effector site are contained in a single molecule, what are the two possibilities for the effector? Give examples for each (1 example for each)

A
  1. Effector is an enzyme (e.g. Tyrosine kinase with epidermal growth factor, insulin)
  2. Effector is an ion channel (e.g. ligand-gated Na channel: Nicotinic acetylcholine receptor)
73
Q

True or false: most kinases are tyrosine kinases

A

False, most kinases are Ser and Thr kinases

74
Q

When the membrane receptor and effector site are two separate molecules couple by a third molecule (e.g. a G protein), what are the two possibilities for the effector? Gives 2 examples for both

A
  1. Effector is an enzyme (adenylyl cyclase, e.g. activated from TSH)
  2. Effector is an ion channel (K+ channel involved in somatostatin stimulation, Ca2+ channel involved in epinephrine stimulation; both are coupled to a GPCR)
75
Q

What 3 domains do tyrosine kinase receptors (RTK) consist of?

A
  1. A single protein chain with extracellular domain that binds the hormone
  2. A single transmembrane region of 20-22 amino acids (usually in helical structure, usually contain a lot of Leu resideus)
  3. An intracellular domain that has a tyrosine kinase catalytic domain (which is usually inactive, but activated by a conformation change).
76
Q

What 2 subunits do insulin and insulin-like growth factor-I (IGF-I) RTK consist of?

A
  1. An alpha subunit that is extracellular and contains a ligand binding site
  2. A beta subunit that has extracellular, transmembrane and intracellular domains
    These subunits are bound covalently to each other.
77
Q

What is the pathway for activation of RTK with intrinsic kinase activity? 4 steps

A
  1. Hormone binding to extracellular domain
  2. Dimerization
  3. Activation of tyrosine kinase in the intracellular domain
  4. Autophosphorylation (kinase flips over and phosphorylates itself)/Trans-phosphorylation (monomers of the dimer phosphorylate each other) of the receptor
78
Q

After phosphorylation of the RTK, what happens next? 3 steps

A
  1. Activation of mitogen-activated protein kinase (Map kinase)
  2. Phosphorylation of transcription factors (activates the transcription factors)
  3. Biological response (increased cell division)
79
Q

Describe an example of the effector being an ion channel, involving a membrane-receptor where the receptor and effector site are contained in a single molecule

A

Ligand-gated Na+ channel, e.g. Nicotinic acetylcholine receptor (nACH-R)
- 5 subunits, 2 α (has a ligand-binding domain for acetylcholine) β, γ, σ, that form a donut structure within the membrane
- α-bungarotoxin can bind the channel and act as an inhibitor of acetylcholine. Causes paralysis because it binds more strong than acetylcholine.

80
Q

In GPCRs, what three separate components are required to generate a signal?

A
  1. The receptor
  2. The enzyme (e.g. adenylate cyclase or phospholipase C)
  3. A coupling protein (e.g. G protein)
81
Q

How many transmembrane domains in a GPCR?

A

7

82
Q

What are the three types of G proteins?

A
  1. Gs
  2. Gi
  3. Gq/11
83
Q

Gs effect on adenylate cyclase, calcium channel and K channel

A
  • Stimulation of adenylate cyclase
  • Activates both ion channels
84
Q

Gi effect on adenylate cyclase and phosphodiesterase

A
  • Inhibits adenylate cyclase
  • Stimulates phosphodiesterase
85
Q

Gq/11 effect on phospholipase C β

A

Stimulates phospholipase C β

86
Q

G protein is composed of ____ subunits, alpha, beta and gamma, which dissociates into _____ following ______

A

G protein is composed of 3 subunits, alpha, beta and gamma, which dissociates into alpha + beta-gamma following interaction of hormone with the receptor.

87
Q

The G protein is a…

A

heterotrimer

88
Q

Which subunit in G proteins activates the effector enzyme such as adenylate or protein kinase C?

A

alpha

89
Q

What specifically allows the GPCR to bind to the G protein?

A

Conformation change upon hormone binding

90
Q

G protein bound to GDP is…

A

Inactive

91
Q

G protein bound to GTP is…

A

Active

92
Q

Adenylate cyclase converts _____ to _____

A

ATP to cAMP

93
Q

Activation of adenylate cyclase is through which G protein?

A

Through Gs

94
Q

Activated Gs can also be written as…
Activated adenylate cyclase can also be written as…

A

-*αs
- *C.αs

95
Q

All steps of adenylate cyclase activation all together (8 steps)

A
  1. Hormone binds GPCR
  2. G protein exchanges GDP for GTP and is activated, and associated with GPCR
  3. Alpha subunits dissociates and activates adenylyl cyclase
  4. GTP is hydrolyzed to GDP and G protein is inactivated.
  5. Adenylyl cyclase changes ATP to cAMP
  6. cAMP activates cAMP-dependent protein kinase (PKA)
  7. PKA phosphorylates serine and threonine residues on target proteins
  8. Biological response
96
Q

Describe the structure of cAMP-dependent protein kinase in its inactive form

A

Has two regulatory subunits each bound to one catalytic subunit

97
Q

What subunits does cAMP bind to in order to activate cAMP-dependent protein kinase?

A

2 cAMP molecules bind to the 2 regulatory subunits. The two catalytic subunits dissociate, and these PKA subunits are active to phosphorylate target proteins.

98
Q

What enzyme inactivates cAMP after it’s done activated the cAMP-dependent protein kinases?

A

Phosphodiesterase

99
Q

If you have a compound that inhibits phosphodiesterase, what would be the biological response as a result?
What’s an example of this?

A

Greater [cAMP], so greater phosphorylation of cellular proteins and biological response
Ex: Viagra inhibits phosphodiesterase Type 5, so high [cGMP] concentration results in relaxation which leads to an erection

100
Q

How does phosphodiesterase inactivate cAMP?

A

Inactivates cAMP by hydrolyzing the cyclic ring to 5’AMP

101
Q

True or false: There’s only one type of phosphodiesterase

A

False
- At least 11 different forms of PDE have been identified. These PDE forms regulate multiple cell functions throughout the body by catalyzing the breakdown of cGMP and cAMP

102
Q

Phosphodiesterase is inhibited by…

A

A family of methylxanthines, i.e. theophylline, caffeine, amenophylline

103
Q

True or false: Phosphodiesterases also inactivate cGMP

A

True

104
Q

Phosphodiesterase type 5 is the predominant enzyme responsible for…

A

cGMP hydrolysis in smooth muscle

105
Q

Activation of PDE 5…

A

Terminates cGMP-mediated smooth muscle relaxation

106
Q

Sildenafil citrate (Viagra)

A

A potent PDE type 5 reversible and selective inhibitor which blocks cGMP hydrolysis effectively

107
Q

Receptors coupled to Gi…
Give an example of a hormone that binds a receptor coupled to Gi

A

Receptors coupled to Gi inhibit adenylate cyclase activity
- E.g. opioids

108
Q

The regulatory component of Gi and its function

A

αl.
- Turns off the active enzyme and prevents the conversion of ATP to cAMP.

109
Q

Gq activates…

A

Phospholipase-Cβ (PLCβ)

110
Q

PLCβ converts _____ to _____

A

phosphatidylinositol 4,5-bisphosphate (ptdIns(4,5)p2 or PIP2) into two potent intracellular messengers, diacylglyceral and inositol triphosphate (IP3)

111
Q

IP3

A

Ligand for an ion channel on the endoplasmic reticulum. Releases Ca2+ from non-mitochondrial intracellular stores (primarily ER) and increases cytoplasmic Ca2+.

112
Q

True or false: Ca2+ levels in a cell are high

A

False. Ca2+ levels in a cell are very low (~0 M) b/c Ca2+ is sequestered into ER (can be liberated) and Golgi (can’t be liberated easily)

113
Q

Steps for PIP2 turnover via Gq/G11 protein

A
  1. Hormone binds receptor and changes GPCR conformation. G protein binds GTP and is activated, and binds GPCR
  2. Active alpha subunit activates PI-PLCβ
  3. PI-PLCβ converts PIP2 into DAG and IP3
  4. IP3 increases intracellular Ca2+ by binding to ligand-gated Ca2+ channels on the ER
  5. Ca2+ and DAG both activate protein kinase C (PKC). PKC is Ca2+-dependent
  6. PKC phosphorylates serine and threonine residues on target proteins
  7. Biological response
114
Q

True or false: Ca2+ levels in cell remain high after release due to IP3

A

False; One Ca2+ is produced, it gets quickly sequestered back after acting on other molecules.

115
Q

True or false: Too much Ca2+ in cells causes death
Explain answer

A

True, because too much Ca2+ restricts muscle movement

116
Q

Increased intracellular Ca2+ content…

A

Modifies activity of various enzymes both in cytoplasm and mitochondria.

117
Q

Name a few targets/functions of Calcium-Calmodulin (12 in total)

A
  1. Phosphodiesterase
  2. Phospholipases
  3. Calcium pumps
  4. Microtubule disassembly
  5. Membrane phosphorylation
  6. Neurotransmitter release (depolarizes cell)
  7. Ca2+-dependent protein kinase I, II
  8. Guanylate cyclase
  9. Phosphorylase kinase
  10. Phosphorylase kinase
  11. Myosin light-chain kinase
  12. Adenylate cyclase
118
Q

True or false: The alpha subunit only phosphorylates/activates adenylyl cyclase and phospholipase C

A

False. The alpha subunit (and the beta-gamma subunit) can also activate ion channels

119
Q

Describe the steps for production of eicosanoids

A
  1. Hormone binds receptor and activates phospholipase A2
  2. Phospholipase A2 converts phospholipids into arachidonic acid
  3. Arachidonic acids are converted into leukotriens (type of eicosanoid), which is catalyzed by lipoxygenase
  4. At the same time, arachidonic acid is converted into prostoglandins, thromboxane A2 and protocycline (which are three examples of eicosanoids) by cyclooxygenase type-II (COX-II)
120
Q

Steroid hormones (as well as/not) thyroid hormones exert their action(s) on (membrane/intracellular) receptors by (activating/not affecting) Gq/G11

A

Steroid hormones as well as thyroid hormones exert their action(s) on intracellular receptors by not affecting Gq/G11.

121
Q

What 4 types of molecules bind to intracellular receptors?

A
  1. Steroids (estrogen, testosterone, cortisol, vitamin D)
  2. Thyroid hormones
  3. Retinoic acid
  4. Peroxisome proliferator-activator (PPAR)
122
Q

What type of hormones bind to tyrosine kinase receptors?

A
  1. Insulin
  2. Epidermal growth factor-1
123
Q

Catecholamines like epinephrine and norepinephrine bind to what type of receptors? What is the effector?

A

G-protein coupled receptors
Effector: Ca2+ channel

124
Q

3 examples of agonists

A
  1. Testosterone (androgen)
  2. Estrogen (17β- Estradiol)
  3. Progesterone (Progestogen)
125
Q

3 examples of antagonists

A
  1. Cyproterone acetate (anti-androgen)
  2. Tamoxifen (anti-estrogen)
  3. RU486 (anti-progestogen)
126
Q

Give an example of a hormone that binds to a GPCR coupled to Gs (stimulates adenylate cyclase)

A

TSH

127
Q

Give two examples of hormones that bind to a GPCR coupled to phosphoinositide-specific phospholipase Cβ (PI-PLCβ)

A
  1. GnRH
  2. TRH
128
Q

What class of hormones are catecholamines (e.g. epinephrine and norepinephrine)?

A

Amino acid derivatives

129
Q

Phosphodiesterases are classified as…

A

Phosphoprotein phosphates

130
Q

Gonadotropins are what type of hormone?

A

Steroid hormones

131
Q

The specificity of hormone-receptor interactions are based on…

A

Shape and charge of hormone

ZOOL 461 (11 decks)

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