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Endocrinology > Hormones, Receptors, GPCR > Flashcards

Hormones, Receptors, GPCR Flashcards

1
Q

Multicellular organisms need _____________
- to control 3 things that are all interconnected

A
  • cellular communication!
    1. proliferation: how many cells to make, when to stop
    2. differentiation: what to becomes
    3. homeostasis: a range that depends on context
  • all 3 are interconnected –> overall integration of various signals allows homeostatis
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2
Q

what are the 2 main network/communication systems?
- railway vs air travel?
- speed?

A
  1. nervous system: direct connection between organs –> railway/car BUT way faster than blood travel
  2. endocrine system: sending chemical messages (hormones) into the circulation –> air travel (obstacles don’t matter) –> can access basically everywhere, but blood flow is slower than neuronal ocmmunication
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3
Q

what is the classical definition of a hormone?
- what does it mean in Greek?
- who is the father of endocrinology? + student?

A
  • chemical messenger released by one type of cells and carried into the bloodstream (circulation) to act on distant target cells
    *until then, thought that all communication was neuronal
  • “I excite” or “I arouse” or “to set in motion”
  • Ernest Starling, with William Bayliss
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4
Q

what is the general definition of a hormone?
- give examples (5)

A
  • chemical messenger (released) from one cell to act on another cell –> doesn’t necessarily need to go into circulation, can just be in extracellular space
  • growth factors, cytokines/chemokines, neurotransmitters, mitogens/morphogens, membrane bound/ECM ligands
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5
Q

what is endocrinology?
- “endo” = ?
- “krine” = ?
- “endocrine” = ? –> fits with classical or general definition of a hormone?

A
  • branch of physiology: study of endocrine glands and hormones
  • “endo” = internal
  • “krine” = secretion
  • “endocrine” = internal secretion
  • fits with classical definition of hormone
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6
Q
  • homeostasis is achieved by a complex _________ network
  • human adult is composed of about ## million/billion/trillion cells
  • these cells are coordinated by less than 24 000_________ encoding ______
  • the coordination is achieved by ________
  • our understanding of these regulatory networks is still _________
A
  • communication network
  • 50 trillion cells
  • 24 000 proteins encoding genes
  • networking
  • incomplete
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7
Q

what are the 3 layers of signaling networks?

A
  1. within cells
  2. between groups of cells (tissues)
  3. between tissues
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8
Q
  • networks _______ against change = __________
  • explain
A

networks buffer against change = homeostasis
- even dramatic changes such as knocking out a gene may not change the output Z bc of buffer/redundancy/new interactions

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9
Q

endocrine communication
- signals are generated in ______ cells (_______ _________ cells)
- _______ cells recognize such signals and respond to them
- type of response to a signal differs btw what?
- what happens when a cell is expose to many signals at the same time?

A
  • special cells (hormone producing cells)
  • target cells
  • between cell types (ie liver cell has different response to epinephrine than a muscle cell, depends on the internal machinery of a cell)
  • the cell response is an integrated response to all signals
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10
Q

autocrine vs juxtacrine vs paracrine vs endocrine signaling?

A
  • autocrine: secretion on itself
  • juxtacrine: secretion of neighbouring cells or attached
  • paracrine: secretion within slight distance/within same tissue
  • endocrine: secretion into blood by endocrine gland (classical definition)
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11
Q
  • cells that synthesize hormones may be ______ or (what?)
  • composition of endocrine glands (3)
  • permanent vs transient glands –> examples
A
  • clustered (endocrine glands, entire organ (?)) OR interspaced as single cells in organs (ie liver) (or portions of an organ)
  • parenchyma (secretory cells), blood vessels (from classical definition), no ducts (bc if glands had ducts, they would be exocrine)
    PERMANENT:
  • pituitary, thyroid, adrenal, pancreas
    TRANSIENT:
  • ovarian follicle, corpus luteum, placenta
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12
Q

what are the differences between a protein hormone endocrine cell and a lipid hormone endocrine cell?
*potential exam question!!! recheck recording

A

PROTEIN:
- linear mitochondria
- rough ER for translation
- secretory granules from Golgi complex to store protein hormones
LIPID:
- circular mitochondria
- smooth ER (where steroid genesis takes place)
- lipid droplet to store precursors of lipid hormones
BOTH HAVE:
- lysosomes
- Golgi complex (more important in protein hormone though)

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13
Q

2 general characteristics of hormones

A
  1. very low concentration –> nanogram/mL or picrograms/mL
  2. very specific receptor –> typically one receptor for one hormone
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14
Q

chemical nature of hormones: 3 broad classifications (+ subtypes)

A
  1. Lipids: steroids and eicosanoids
  2. Proteins: short polypeptides and large proteins (chemical modification through glycosylation)
  3. amino acid derivatives (epinephrine, norepinephrine)
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15
Q
  • what is the precursor fo steroid hormones? (specific!)
  • highly __________
  • found where?
  • source (2)
  • 3 derivatives
A
  • cholesterol! contains sterol ring
  • highly hydrophobic –> can directly go in cell = very fast!
  • found in cell membrane
  • source: diet + de novo synthesis
  • vitamin D, bile acid (lipid digestion and signaling), steroid hormones (sex and adrenal steroids)
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16
Q

2 categories of steroid hormones + subtypes

A

ADRENAL
- mineralocorticoids: affects mineral homeostasis
- glucocorticoids: affects glucose metabolism and immune function
GONADS (testis and ovaries):
- estrogens
- progestogens
- androgens

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17
Q
  • what is steroidogenesis?
  • steroidogenic enzymes depend on what?
  • 2 mitochondrial electron transporters
  • 2 microsomal electron transporters
  • what are 2 super important organelles?
A
  • synthesis of steroid hormones from cholesterol
  • electron transfer proteins! –> redox reactions (deoxygenation, hydrogenation)
    MITOCHONDRIAL:
  • ADR: adrenodoxin reductase
  • Adx: adrenodoxin
    MICROSOMAL:
  • POR: P450 oxidoreductase
  • B5: cytochrome b5
  • mitochondria and endoplasmic reticulum!
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18
Q

what are some steroids of important?
- mineralcorticoid (2)
- glucocorticoid (4)
- androgens (2)

A
  • Mineralcorticoid: progesterone, aldosterone
  • Glucocorticoid: 17OH-Progesterone, 11-deoxycortisol, cortisol, cortisone
  • Androgens: androstenedione, testosterone
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19
Q

difference between testosterone and 17b-estradiol?

A
  • double bonded O in testosterone (androgen) VS -OH in 17b-estradiol (estrogen)
  • very subtle changes –> can result in enormous change in signaling
  • 3 dimensional structure of the 2 molecules differs markedly
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20
Q

synthesis of steroid hormones:
- derived from what?
- main source is circulatory ____
- ____ can be taken up and can also be synthesized from ________
- what determines steroid production?
- some enzymes are in _______, some are in ______ _______, some are in ______
- do steroid intermediates shuttle back and forth?
- most steroids differ by minor modifications of ______ _______, often what?

A
  • cholesterol
  • circulatory LDL
  • HDL –> synthesized from acetyl-coA
  • cell specific expression of enzymes (ie enzymes to make testosterone won’t be in adrenal gland)
  • mitochondria (CYP11A1, CYP11B1), endoplasmic reticulum (CYP17A1, CYP21A2), some in both( HSD3B1, HSD17B…)
  • yes! can shuttle between the 2 organelles
  • side groups, often hydroxyl groups (but function differs a lot!)
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21
Q

Eicosanoids:
- metabolites of which ___-C FA? –> that FA comes from what?
- name 4 types of eicosanoids + weird one
- prostaglandins: isolated from ________ + 2 charac

A
  • 20-C FA –> arachidonic acid –> from membrane phospholipid (using enzyme phospholipase A)
  • prostaglandins, prostacyclins, throboxanes, leukotrienes + 12-HETE and 15-HETE (Hydroxy-eicosatetraenoic acid)
  • prostaglandins –> isolated from prostate, inflammatory reaction and reproduction
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22
Q

peptide/protein hormones:
- small/large polypeptides?
- linear or globular?
- contain subunits?
- what is critical for interaction with receptor?
- lipid or water soluble?

A
  • LARGE! bc polymers
  • linear or multiple chains
  • subunits! linked by disulfide bridges
  • 3D structure
  • water soluble = main difference to steroids (lipid soluble)
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23
Q

how are protein hormone synthesized?

A
  • nothing but gene expression!
  • transcription –> translation –> post-translational modification
    (ie: cleaving long aa chain (preprohormones) to generate small peptide hormones (GnRH, oxytocin, TRH), interaction and linking subunits, 3D structure)
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24
Q

what are post transcriptional modifications to peptide hormones? (3)

A
  • 5’ capping
  • splicing of introns, cleavage
  • polyadenylation
25
Q

translation of peptide hormones:
- start codon? codes for which aa?
- initiation?

A
  • AUG –> methionine
  • tRNA charged/aminoacylated with met bind to small ribosomal unit and scan mRNA until they find AUG –> large subunit comes –> elongation until stop codon
26
Q

how can 1 gene become 2 different proteins?
- ie with calcitonin

A

post-transcriptional modification! –> alternative splicing: pick and choose CALCITONIN:
- thyroid: becomes calcitonin
- brain: becomes calcitonin gene related protein (CGRP) bc not same exons

27
Q

post-translational modification
A. ____________ –> what is cleaved off + _____ protein is ___________ (why?) –> becomes ____________
B. 4 different modifications (probs not that important…)

A

A. preprohormone –> signal peptide is cleaved + sequestered protein is glycosylated (affects half-life + how signal is transduced–> pro-hormone
B1. prohormone –> disulphide bond formation and/or cleavage of amino-terminal pro-hormone sequence –> ie growth hormone
B2. polyprotein –> multiple processing + post-translational cleavage –> POMC = ACTH and MSH, pro-glucagon = glucagon and GLP 1/2
B3. prohormone: orientation of functional peptides (remove a part) –> ie insulin, relaxin
B4. 2 subunits (alpha and beta) from 2 different genes assemble + further glycosylation to form 1 hormone –> ie thyroid stimulating hormone luteinizing hormone

28
Q

post-translational peptide modifications:
- what sequence is cleaved by peptidase –> to form what?
- formation of _______ _____ btw _____ + ___________
- transport by ______ into which organelle? further (2)
- packaging into ______, sometimes together with what?

A
  • lipophilic leader sequence (signal peptide) –> cleaved by peptidase to form pro-hormone
  • formation of disulfide bridges between cysteines + glycosylation
  • vesicles into Golgi apparatus –> further glycosylation and proteolytic cleavage
  • packaging into vesicles (sometimes not fully ready yet), sometimes together with activating peptidase
29
Q

what are the 2 categories of tyrosine derivatives + examples

A

THYROID HORMONES:
- thyroxine (T4)
- triiodothyronin (T3)
ADRENAL MEDULLA:
- epinephrine
- norepinephrine
- dopamine
- often used as neurotransmitters

30
Q
  • which hormones are stored?
  • where are they stored?
  • movement to cell membrane is mediated by (2)
  • cells require ______ to activate and release (action?) the stored prohormone
A
  • hydrophilic hormones
  • in secretory vesicles (granules/pockets of organelles coming from ER) in the cytoplasm
  • microtubules (cytoskeleton) and microfilament
  • stimulus to activate and release (exocytosis)
31
Q

hydrophobic vs hydrophilic hormones
- examples (2 each)
- storage after synthesis?
- binding proteins for transport?
- half-life?
- receptors?
- mechanism of action (direct or indirect)

A

HYDROPHOBIC:
- steroids and thyronines
- minimal storage except for thyronines –> synthesis when necessary
- always transported along with carrier/binding protein through blood
- long (hours or days bc always bound to smtg = harder to degrade)
- cytoplasmic or nuclear (but also some surface receptors)
- direct
HYDROPHILIC:
- peptides and catecholamines
- almost always stored
- sometimes binding proteins, especially smaller peptides
- short half-life (minutes) –> easily degraded
- plasma membrane receptors
- indirect (second messenger)

32
Q

what 3 things control synthesis and secretion of hormones? + explain ish

A
  1. neural inputs
    - brain + hypothalamus
  2. hormonal stimulation/inhibition
    - releasing factors/hormones
    - inhibitory factors
    - feedback system
  3. metabolic status
    - stress
    - blood concentrations of substances (Ca, glucose, water)
33
Q

Response of a cell to a signal/signals
- 3 signals (A, B and C) to cell –> tells is to survive –> fate of a cell depends on a __________ of _________ signals
- what if i want the cell to divide? or differentiate?
- what happens for cell to die?

A
  • fat of cell depends on a multitude of extracellular signals
  • signals A, B and C (for survival) + signals D and E (for division)
  • signals A, B and C (for survival) + signals F and G (for differentiation)
  • if signals are absent (no signal at all) –> most cells undergo programmed death = apoptosis
34
Q

Response of a cell to a signal
- what is the extracellular signal?
- what recognizes the signal? how?
- recognition leads to change of what? –> leads to activation of what? = ________ ________

A
  • extracellular signal molecule = chemical signal = ligand (smtg that comes from outside and binds to receptor)
  • a receptor protein! –> signal binds/attaches to its receptor = recognition
  • leads to change of intracellular network of proteins –> signal mediators (transduce signals by interacting with lower level mediators) –> activation of target genes or proteins = cellular response
35
Q

what are examples of cellular response from signal transduction?
- what do the multiple levels of signal transduction allow?

A
  • altered metabolism, altered gene expression, altered cell shape or movement, secretion…
  • allows amplification of signal at each level! can be exponential
36
Q

Hormone action
- often the signal is ________ amplified during transmission and results in an ______ or _____ stage
- do multiple signaling proteins interact with target proteins?
- modified target proteins alter the ________ of the cell + trigger a feedback circuit that does (smtg) or (smtg)

A
  • exponentially amplified –> results in an on or off stage
  • one or more interact with target proteins (ie key regulatory proteins that determine the properties of a cell)
  • the properties of the cell + trigger feedback circuit that shuts off the receptor OR removes it from the cell surface
37
Q

what are the 2 main classes of signal receptor pathways?
- what type of signal?

A
  1. pathways with cell-surface receptors –> hydrophilic signal molecule
  2. pathways with intracellular receptors –> hydrophobic signal
38
Q

what are the exceptions to the fact that hydrophilic hormones have cell surface receptors and hydrophobic hormones have intracellular receptors? (3)

A
  1. lipid hormones, prostaglandins and leukotrienes have cell surface receptors (we don’t know if they have intracellular receptors)
  2. many steroids and bile acids have both intracellular and cell surface receptors
  3. recent development: many metabolites have receptors and thus can function as hormones (so chemical signals don’t have to be proteins or lipid hormones)
39
Q
  • what is a domain?
  • what are the 3 main domains of a cell surface receptor?
    1. ___________
  • which end of prot?
  • water/fat soluble
  • what happens there?
  • rich in what?
  • often what?
    2. ______ _______ domain
  • shape?
  • what is needed to do its function ish?
    3. _______ domain
  • function?
  • water/fat soluble
  • which end of protein?
A
  • domain = name attributed to a part of a protein that does a specific function/give a specific structure/at a specific location
    1. ectodomain
  • amino end of protein
  • water soluble
  • signal binds there
  • rich in cysteine residues (S-S bonds for folding –> gives 3D shape so signal can lock in)
  • often glycosylated
    2. hydrophobic transmembrane domain:
  • alpha helix
  • water/fat soluble
  • 20-25 aa needed to cross membrane once
    3. cytoplasmic/intracellular domain:
  • relays signal from outside to inside
  • water soluble
  • carboxyl end of protein
40
Q

free ectodomain may circulate as what?
- useful in _______
- useful for ________
- ex?

A
  • circulate as hormone binding protein
  • useful in research: put ectodomain of a known ligand onto a receptor with unknown function
  • useful for transport
    ex: GH receptor’s ectodomain acts as a GH binding protein
41
Q
  • the activated cytoplasmic domain induces a _______ ________ –> relay of ___a_____ ____b____ of signaling proteins
  • such ___a_____ ____b____ are induced by (2)
  • which is more common btw the 2?
A
  • induces a signaling cascade –> relay of conformational changes of signaling proteins
    1. phosphorylation of proteins –> much more common and much better understood!
    2. binding between proteins
42
Q

mostly which 3 aa are modulated by phosphorylation? why?

A
  • serine, threonine and tyrosine
  • bc polar hydroxyl group (OH) –> easily exchanged with a phosphate group = phosphorylation
43
Q
  • what is phosphorylation?
  • catalyzed by what?
  • reversed by what?
  • when phosphorylated protein 1 catalyzes phosphorylation of a 2nd protein, what provides the phosphate group?
  • each phosphorylation step allows for signal _________
A
  • OH of an aa replaced by PO4 from ATP
  • kinases
  • phosphatases: removes PO4 and puts back OH
  • ATP provides phosphate group! not the previously phosphorylated protein –> so each reaction is energy dependent
  • signal amplification
44
Q
  • are phosphorylated serine & threonine more or less abundant than phosphorylated tyrosine? give ratio
  • tyrosine phosphorylation often occurs at beginning/middle/end of cascade
  • phosphorylated tyrosine serves as a ______(a)____ site for downstream signal proteins (ie?)
  • the aa that mediates ____(a)_____ to phosphorylated tyrosine is _______ and __________ for proteins involved in signaling cascade
A
  • serine:threonine more abundant! (100: 1 tyrosine)
  • beginning!
  • docking sites! ie SH2, SH3 domains
  • mediates docking –> is conserved and diagnostic for …
45
Q

what are the 3 types of cell surface receptors?
- one has 2 subtypes

A
  1. G-protein coupled receptors (GPCR)
  2. Tyrosine Kinase Receptors (RTK) –> intrinsic vs recruited TK activity
  3. Serine-threonine kinase receptors (RSTK)
46
Q

explain the 7 steps of GPCR PKA singaling
- using epinephrine as the signal

A
  1. epinephrine binds to its specific receptor (b-adrenergic receptor)
  2. hormone-receptor complex causes GDP bound to Ga to be replaced by GTP, activating Ga
  3. activated Ga separates from Gbz, moves to adenylyl cyclase (already bound to membrane) and activates it. many Ga subunits may be activated by one occupied receptor
  4. adenylyl cyclase catalyzes formation of cAMP from ATP
  5. cAMP activates PKA
  6. phosphorylation of cellular proteins by PKA causes cellular response to epinephrine
  7. cAMP is degraded, reversing activation of PKA
47
Q
  • why G protein named like that?
  • what is the 2nd messenger in the GPCR pathway?
  • how many times does the GPCR pass through the lipid membrane?
A
  • because it is modulated by guanosine (GDP/GTP)
  • ATP –> adenosine 3’,5’-cyclic monophosphate (cAMP) using adenylyl cyclase enzyme
  • 7 passes!
48
Q

protein kinase A
- always exists as a _________
- 2 subunits? + functions
- how is it activated?

A
  • dimer!
    1. catalytic subunit catalyzes kinase activity/phosphorylation
    2. regulatory subunit regulates catalytic subunit by blocking the substrate binding cleft of the catalytic subunit
  • 2 cAMP on regulatory subunit of each dimer (so 4 in total) –> results in change of conformation and substrate binding cleft of catalytic subunit now available for substrate
49
Q

what are some cellular proteins regulated by cAMP-PKA?

A
  • glycogen synthase –> glycogen synthesis
  • phosphorylase b kinase –> glycogen breakdown
  • pyruvate kinase –> glycolysis
  • pyruvate dehydrogenase complex –> pyruvate to acetyl-coA
  • hormone-sensitive lipase –> TG mobilization and FA oxidation
50
Q

explain the 4 steps of desensitization/resensitization cycle of GPCR
- which part is desensitization and resensitization?

A
  1. Gbz recruits b-adrenergic receptor kinase (bARK) to the membrane where it phosphorylates Ser residues at the carboxyl terminus of receptor (cytoplasmic domain)
  2. b-arrestin (barr = protein) binds to the phosphorylated carboxyl terminal domain of the receptor
  3. receptor-arrestin complex enters the cell by endocytosis
  4. in endocytic vesicle, arrestin dissociates; receptor is dephosphorylated and returned to cell surface
    - desensitization = bring it inside cell
    - resensitization = bring it back on membrane
51
Q

do bARK and bArr only work with epinephrine?

A

no! they work with GPCRs in general!

52
Q

which scenario lights up with dots? vs normal light
1. normal cell + Rhodamine-TRH
2. normal cell + green fluorescent light + arrestin
3. cell without cytoplasmic domain + Rhodamine-TRH
4. cell without cytoplasmic domain + green fluorescent light + arrestin

A
  1. normal light
  2. lights up with dots! bc arrestin needs cytoplasmic domain!
  3. normal light
  4. normal light –> GFP doesnt light up bc no cytoplasmic domain for arrestin to attach to
53
Q

what are 5 ways in which target cells can become desensitized to a signal molecule?

A
  1. receptor sequestration (move away from cell surface, but can be recycled)
  2. receptor down-regulation (sequestration + degraded by proteins)
  3. receptor inactivation (ie repressor binds to cytoplasmic domain to repress signal transduction)
  4. inactivating of signaling protein
  5. production of inhibitory protein (negative regulator is induced)
54
Q

Gs alpha vs Gi a vs Gq a vs Goa alpha vs G12/13a

A
  • Gs = stimulatory = activates adenylate cyclase
  • Gi = inhibitory = inhibits adenylate cyclase
  • Gq = activates phospholipase C (IP3 and DAG and Ca signaling)
  • Goa = activates ion channels
  • G12/13 = regulate actin cytoskeleton
55
Q

explain the 7 steps of GPCR signaling through IP3 and Ca

A
  1. hormone binds to a specific receptor
  2. occupied receptor causes GDP-GTP exchange on Gqa
  3. Gqa with bound GTP moves to phospholipase C and activates it
  4. active PLC cleaves PIP2 (in membrane) to IP3 (2nd messenger) and diacylglycerol (in membrane)
  5. IP3 binds to specific receptor-gated Ca2+ channel (also GPCR), releasing sequestered Ca2+
  6. diacylglycerol + Ca2+ activate protein kinase C at the surface of plasma membrane
  7. phosphorylation of cellular proteins by protein kinase C produces some of the cellular responses to the hormone
56
Q

what is PIP2? –> cleaved to what (2) by what?
- which is the 2nd messenger?

A
  • PIP2 = phosphatidylinositol 4,5-bisphosphate
  • cleaved to 1,2 diacylglycerol (DAG) (stays in membrane) + inositol 1,4,5-trisphosphate (IP3) (2nd messenger = can go in cell)
  • cleaved by phospholipase C
57
Q
  • can hormones use Gs protein and Gq protein? and Gi protein
  • G protein use may change during ________ and depending on (2)
A
  • yes! hormones may use more than one G protein
  • during development + depending on hormone concentration or in different tissues
58
Q
A

Endocrinology (14 decks)

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