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Biochemistry > Yokomori 1 > Flashcards

Yokomori 1 Flashcards

1
Q

hi

A

you lame

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2
Q

Briefly outline the signalling pathway and the 3 major outcomes.

A

1) ligand to receptor
2) activates intracellular signaling proteins
3) activates metabolic enzyme, gene regulatory protein, or cytoskeletal protein

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3
Q

What are the different ways of ligand and receptor interact/presented?

A

1) signaling by secreted molecules
2) signaling by plasma-membrane bound molecules

  • cell surface receptors receive HYDROPHILIC molecules (hydrophilic hormones->peptide hormones ie insulin, growth factors, or small charged molecule like histamine, epinephrine)
  • intracellular receptors receive HYDROPHOBIC molecules (lipophilic hormones->steroids,retinoids,fatty acid deriv.)
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4
Q

What are the different types of cell signaling?

IMPORTANT

A

1) Paracrine - short range, short life on molecules; localized. DEVELOPMENTAL SIGNALING - TGFBeta
2) Synaptic - use neurotransmitter to travel “synapse”
3) Endocrine - HORMONE signaling, long life and long range (use bloodstream to target multiple tissues)
4) Autocrine - cells respond to ligand by releasing ligand as well (feedback); COMMUNITY EFFECT (so identical cells have same developmental decisions) ie GROWTH FACTORS
5) Gap junction - involves community effect as well. muscle, neuron, epithelial cells, early development

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5
Q

What are the characteristics of endocrine signaling?

A
  • long duration because of long half life
  • slow response because uses blood flow
  • prolonged signaling because tight binding

SLOW AND PROLONGED RESPONSE

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6
Q

What are the characteristics of synaptic signaling?

A
  • low affinity receptor

- RAPID RESPONSE AND TERMINATION

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7
Q

What are the important features of signal transduction?

A
  • reversible
  • amplification processes
  • different pathways interact
  • one ligand can activate multiple receptors and pathways
  • presence of homologous signaling molecules with overlapping and distinct fxns
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8
Q

Describe signaling by phosphate transfer. Signaling by nucleotide exchange. Reversible?

IMPORTANT

A

1) signal activates protein kinase (uses ATP) to phosphorylate (ON). Remove phosphate with phosphatase (OFF)
2) GTP binds (ON), GTP hydrolysis to GDP (OFF)

YES, IT IS REVERSIBLE

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9
Q

Give an example of signal amplification.

A

Activation of kinases leads to Ca2+ release.

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10
Q

What is signaling crosstalk? (target sharing)

A

Two different signaling pathways activated by different hormones both activate the same target. (block of one means other pathways can still be used)

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11
Q

Give an example of a ligand that evokes different responses in diff cell types.

A

Acetylcholine.
in heart - decreased rate and force of contraction
in skeletal muscle - contraction
in salivary gland cell - secretion

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12
Q

What are the 3 major classes of cell surface receptors? IMPORTANT

A

1) ion channel linked receptors
2) G protein coupled receptors
3) enzyme linked receptors

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13
Q

What is an ion channel linked receptor?

A

Binding of ligand alters conformation of receptor -> allows specific ion to flow -> results in electric potential across cell membrane ie. acetycholine receptor in nerve-muscle junction

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14
Q

What is G protein coupled receptor?

A

Ligand binding activates trimeric G protein, activates/inhibits enzyme that generates a second messenger or modulates ion channel

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15
Q

What is enzyme-linked receptors?

A

Receptor with enzymatic activity (ie receptor tyrosine kinases, TGFBeta receptors)

Receptors associated with enzymes. Receptors don’t have catalytic activities but ligand binding stimulates formation of dimeric receptor which then activates protein-tyrosine kinases. ie. cytokine receptors

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16
Q

What type of receptor are nuclear receptors? Ligands?

A

They are intracellular receptors, use small lipophilic hormones. The receptors can act as TRANSCRIPTION FACTORS in the nucleus

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17
Q

What does NR signal?

A

1) development
2) cell differentiation
3) organ physiology
4) homeostasis

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18
Q

What is retinoid X receptor? (RXR)

A

Binding partner for other non-steroid hormone receptors (remember that steroid hormone receptors bind as homodimers in the presence of ligands but non steroid receptors bind as heterodimers)

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19
Q

How can NR superfamily be grouped?

A

1) subfamily: ie. RAR subfamily within steroid receptor family
2) subtypes: products of individual genes (ie. RAR-alpha, RAR-beta)
3) isoforms: products of alternative splicing and/or promoter usage (ie. RAR-alph1, RAR-alpha2)

subtypes and isoforms may have redundant and/or distinct functions

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20
Q

What is the general structure of a NR?

A

zinc-finger DNA binding domain, ligand binding/activation domain

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21
Q

Binding is with specific/non specific DNA sequence motif?

A

SPECIFIC

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22
Q

What are the different steroid hormones?

A

aldosterone, cortisol, estrogen, progesterone, testosterone

23
Q

What are the two classes of steroid signaling?

A

Classic: nuclear-initiated steroid signaling (NISS)
Rapid: membrane-initiated steroid signaling (MISS)

24
Q

Briefly describe NISS.

A

Binding of steroid hormone causes conformational change and binding of NR to GRE DNA sequence. Hormone receptor complex regulates transcription.

25
Q

Briefly describe MISS.

A

BInding of steroid hormone to receptor on outer plasma membrane causes activation of signaling protein (ie. G protein, typrosine kinase) which activates a kinase to phosphorylate and induce rapid response of target proteins (Ie. ion channels)

26
Q

What is the role of glucocorticoid receptor? (GR)

A

Fxns in regulation of carbohydrate (glucose), protein and lipid (fat) metabolism. Also modulates immune (anti-inflammatory and immunosuppressive action) and CNS responses (mood+cognitive fxns).

27
Q

What is the hypothalamo-pituitary-adrenal axis (HPA axis) pathway?

A

regulation of glucocorticoid production in response to stress

28
Q

How does HPA axis work?

A

1) Stress triggers release of vasopressin (AVP) and corticotropin releasing factor (CRF) by hypothalamus
2) This stimulates release of adrenocorticotropic hormone (ACTH) by anterior pituitary
3) ACTH stimulates release of glucocorticoids by adrenal cortex
4) This then goes on to affect tissues

29
Q

How is HPA axis regulated?

A

negative feedback by glucocorticoids that directly inhibit ACTH and CRF release

ACTIVATED by stress

30
Q

What happens following release of glucocorticoids?

A

fxn through GR to coordinate immune, nervous, and endocrine response such as:

1) enhanced transcription of gluconeogenic enzymes in liver
2) increase lipolysis in adipocytes
3) suppress glucose uptake in tissue
4) stimulation of feeding behavior in CNS
5) immune suppression

31
Q

What is cushing syndrome?

A

hypercortisolism (too much glucocorticoid)

  • result of adrenal hyperplasia (overproduction of ACTH), adrenal neoplasia, and iatrogenic causes (prolonged use of glucocorticoid)
  • causes obesity, HT, osteoporosis, and diabetes
  • caused primarily by pituitary tumor that overproduces ACTH
32
Q

What is gene knock out? knock in? conditional knock out?

A

knock out removes gene
knock in is targeted gene mutation
conditional knock out removes gene from specific tissue or condition

33
Q

What happened to the GR mouse models?

A

1) knock out mice: died b/c of respiratory failure due to lack of inflation of lungs (def of glucocorticoid inducible sodium channel)
2) knock in mutant (targeted gene mutation) mice: point mutation in zinc finger leads to def in dimerization and DNA binding. Mutant survived; DNA binding is not essential
3) Conditional knock-out of GR gene in nervous system: knowing out GR was not lethal, but HPA axis disrupted; indicates negative feedback of HPA axis requires GR expression; high lvl of glucocorticoid in blood like cushing’s; knockout mice were less anxious - evidence of role of GR in anxiety and learning

34
Q

How does the mineralocorticoid (aldosterone) receptor (MR) work? What might a defect cause?

A

Fxns in Na+ reabsorption.

  • MR expressed in kidney causes absorption of salt and water for release back into blood
  • Mutation in MR cause early-onset HYPERTENSION
  • familial early-onset hypertension: mutation of MR makes it hyperactive and broadens ligand specificity
  • women with MR mutation get HT during pregnancy (gestational HT, can lead to preeclampsia) b/c increased progesterone binds and activates MR
35
Q

What are the sex hormones? receptors?

A

estrogens, progesterone, or androgen (testosterone)

  • develop sex characteristics and reproductive fxns
  • estrogen receptors (ER): male knockout mice are infertile. ER has direct role in spermatogenesis
  • androgen receptors (AR): androgen insensitivity syndrome (AIS): caused by defect in AR
  • causes abnormality of male phenotypic development; infertile
  • plays crucial post-meiotic role in functional sperm production
  • aside from AIS, defect in AR can also lead to Kennedy’s disease and prostate cancer (PCa)
36
Q

What is Kennedy’s disease?

A

Spinal and bulbar muscular atrophy (SBMA).

  • adult-onset neurodegenerative disease
  • muscle weakness and atrophy
  • caused by expansion of CAG repeat which encodes polyglutamine tract in AR gene
  • occurs in adult males (females asymptomatic)
37
Q

What is prostate cancer? (PCa)

A

AR has central role in normal growth of prostate; hormonal therapy to reduce androgen is effective
-during therapy an incurable highly aggressive androgen independent (AI)- or hormone refractory disease will emerge; this causes abnormal activation of AR

38
Q

What are non-steroid hormone receptors?

A

heterodimeric receptors; type II receptors
ie: thyroid hormone receptor (TR)
vitamin D receptor (VDR)
retinoic acid receptor (RAR)
-all heterodimerize with RXR (retinoid X receptor)
-resides in the nucleus and are bound to their responsive DNA element in the absence of ligands
-receptors are repressors with no ligand, activators with ligand
-activation DOES NOT REQuIRE RXR ligand; 9-cis retinoic acid

39
Q

What is the mechanism for transcriptional regulation by non steroid hormone NR.

A

Ligand (-), corepressor HDAC is bound (histone deacetylase); represses expression
Ligand (+) coactivator HAT is bound (histone acetyltransferase); activates expression

HDAC: deacetylates histone tail, causes tight binding to DNA
HAT: hyperacetylates histone tail, causes repulsion from DNA

40
Q

What is TR? (thyroid hormone receptor)

A
  • control rate of metabolism
  • general resistance to thyroid hormone (GRTH) syndrome
  • high circulating levels of thyroid hormones
  • hearing defect, mental retardation, emotional disturbance
41
Q

What are the diff thyroid hormones?

A

hypothalamus - TRH
pituitary - TSH
thyroid - thyroxine (T4) and triiodothyronine (T3)

42
Q

what causes hyperthyroidism? thyroid storm?

A
  • Grave’s disease (overactivity of thyroid gland)
  • excessive intake of thyroid hormones or iodine
  • excess TSH

hyperthyroidism can lead to thyroid storm (thyrotoxic crisis)

  • life threatening
  • clinical presentation: fever, rapid heart rate, irregular heart beat, dehydration
  • treatment is to decrease thyroid hormone levels and synthesis
  • PTU and methimazole can decrease synthesis
43
Q

Describe VDR (vitamin D receptor)

A
  • Ca 2+ homeostasis, vitamin D metabolism
  • mutations associated with hypocalcemic vitamin D-resistant rickets (mineralization defect) and loss of hair
  • rickets cause softening of bones (leads to fractures)
  • children not getting enough sun can be cause
  • also can cause hypocalcaemia and hyperparathyroidsim
44
Q

WHat are RAR for? (retinoic acid receptor)

A
  • development and cellular differentiation
  • RAR knockout mice exhibit vitamin A deficient syndromes: development defect + cancer
  • chromosome translocations involving RAR gene can cause acute promyelocytic leukemia (APL); caused by RAR fusion proteins (messes with expression and repression of genes)
45
Q

What is unique about the orphan receptor LXR activation?

A

LXR/RXR dimer can be activated by LXR ligand (oxysterol) or RXR ligand (9-cis retinoic acid) or both ligands synergistically

46
Q

How is cholesterol homeostasis maintained?

A

Cholesterol is used to make oxysterol (ligand for LXR). Oxysterol can also act to inhibit the SREBP (sterol regulatory element binding proteins) gene which activates cholesterol synthesis (feedback inhibition)

(Mechanism for SREBP cleavage) When there is cholesterol around, SREBP (in ER lumen) interacts with SCAP and Insig-1(2); lack of cholesterol disrupts this interaction between SCAP and Insig-1(2) which causes SREBP to bud off to golgi and eventually to the to nucleus.

47
Q

How does oxysterol act in a feed forward mechanisM?

A

When too much cholesterol is consumed, feed-forward pathway activated to eliminate cholesterol as BILE ACIDS. Involves cholesterol 7a-hydroxylase (Cyp7alpha); rate-limiting enzyme in bile acid synthesis
-Upregulation of Cyp7alpha activated by LXR; activated by cholesterol produced oxysterol

48
Q

WHat happens in LXR alpha knock-out mice

A

LXRa knock out are ok on low cholesterol diet

  • rich cholesterol diet shows no increase in bile acid synthesis and excretion
  • results in chronic hepatomegaly and impaired liver function due to cholesterol accumulation
49
Q

What does FXR detect?

A

Detects level of bile acid and regulates expression of genes for bile acid synthesis and secretion

50
Q

WHat is PPAR? LIgands?

A

peroxisome proliferator-activated receptors: lipid sensors

  • ligands: fatty acids and FA metabolites
  • involved in diabetes, obesity, atherosclerosis, and cancer
51
Q

What is PPAR-alpha? Targets? Ligands?

A
  • lipid metabolism
  • expressed in liver, kidney, heart, and muscle
  • target genes: FA uptake, FA binding in cells, FA catabolism, lipoprotein assembly
  • ligand: (natural) FA and eicosanoids such as leukotriene
    (synthetic) fibrates (reduction of high TAG levels)
  • PPAR-alpha knock outs: abnormalities in TAG and cholesterol metabolism, do not respond to fibrates; obese with age
52
Q

What is PPAR-gamma? Targets? Ligands?

A

glucose and lipid homeostasis; adipocyte differentiation

  • expressed in ADIPOCYTES, large intestine, cells of monocyte lineage
  • target genes: genes in lipogenic pathways
  • ligands: (natural) FA and eicosanoids such as prostaglandin
    (synthetic) TZDs (thiozolinediones) used for treatment of type II diabetes
  • PPAR gamma knock out mice: embryonic lethal. Stem cells can differentiate into adipocytes
  • mutation in humans: abnormality in fat storage (obesity) and insulin response
53
Q

What do PXR (pregnane x receptor) do?

A

xenobiotic sensor

  • regulates genes important for detox of harmful xenobiotics (pollutants, carcinogens, and drugs)
  • expressed in liver and intestine
  • target gene: cytochrome P450 (CYP)
  • mediator of drug-drug interactions: upregulates CYP3A4 (involved in metabolism of 50% of all drugs)
54
Q

what are the different orphan receptors used in maintaining homeostasis?

A

1) LXR-oxysterols: cholesterol sensor
2) FXR-bile acids: bile acid sensor
3) PPAR-fatty acids/eicosanoids: fatty acid/eicosanoids sensor
4) PXR-steroid derivatives: xenobiotic sensor

Biochemistry (12 decks)

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