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NEUROSCIENCE 2 > CAH > Flashcards

CAH Flashcards

1
Q

What are steroid hormone receptors?

A
  • found within the cell, typically in cytoplasm or nucleus
  • ligands are small lipophilic molecules
  • receptor encoded by a single gene
  • able to bind to DNA
  • function as transcription factors
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2
Q

How do steroid hormones work?

A
  • most hydrophobic steroid are bound to plasma protein carriers as they cannot travel in water, only unbound hormones can diffuse into target cell
  • bind to receptor that use secondary messengers
  • receptor-hormone complex binds to DNA and activates or represses one or more genes
  • activated genes create new mRNA –> protein synthesis
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3
Q

What are type 1 nuclear receptors and how do they work?

A
  • work as homo-dimers
  • normally found in cytoplasm
  • e.g. glucocorticoids, mineralocorticoids, androgens
  • when hormone binds, move from cytoplasm to uncles and bind to sequence of DNA called hormone response elements (HRE’s)
  • nuclear receptor/DNA complex then recruits other proteins which transcribe DNA downstream from HRE to mRNA and eventually protein causing a change in cell function
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4
Q

What are type 2 nuclear receptors and how do they work?

A
  • work at hetero-dimers
  • all bind as heterosexual-dimers with RXR (retinoid X receptor)
  • e.g. VDR (vitamin D), RAR and TR
  • found in nucleus normally bound to response element already
  • these receptors have proteins on them (co-repressors) which stop transcription
  • activated by removing co-repressor when ligand binds
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5
Q

Describe the structure of the steroid hormone receptors

A
  • 3 domains: transactivation, DNA binding and hormone binding
  • within those there are 5 further domains: A,B,C,D,E and sometimes F

A/B: AF-1 = always on, when hormone binds to receptor, AF-2 works with AF-1 to drastically up regulate gene transcription (synergisation)

C/D: DNA binding areas, NLS = nuclear locational signal (allows entry into nucleus to bind to DNA). Hinge that allows dimerisation is here

E: within domain there is AF-2- which is a transcriptional activation domain, becomes active when hormone bound

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6
Q

What is a zinc finger?

A
  • within the C domain
  • enables proteins to bind to DNA
  • second zinc finger domain involved in dimerisation
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7
Q

What are HRE’s?

A

Hormone response elements

  • within receptor there is a set sequence recognition of DNA
  • allow for specificity
  • dimeric and 2 halves for 2 receptors as its dimeric
  • vary in structure
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8
Q

How does a hormone alter gene transcription?

A
  • binding via receptor to target sequences of DNA
  • HRE
  • located in regulatory regions of target gene
  • usually 5’, close to core promoter
  • 6bp hexamer - core recognition motif
  • usually 2 half-sites, intervening base pairs
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9
Q

How does a receptor recognise a specific HRE?

A

P-box contains:

  • zinc fingers which enable DNA docking
  • HRE which allows for specificity
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10
Q

What is ACTH and how is it synthesised?

A

Adrenocorticotrophic hormone - aka adrenocorticotrophin
- polypeptide of 39 amino acids

Synthesis:

  • large precursor Pro-opiomelanocortin (POMC) is the source of several important biologically active substances
  • ACTH = cut from POMC
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11
Q

How is cortisol released in response to ACTH?

A
  • stress = hypothalamus releases CRH (corticotrophin releasing hormone)
  • interacts with receptor to cause release of ACTH
  • interacts with receptor to cause cortisol release from adrenal cortex
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12
Q

What are the effects of ACTH?

A
  • ACTH stimulates G-protein receptor coupled to cAMP
  • this stimulates the enzyme that converts cholesterol to cortisol or sex steroid precursors
  • ACTH rises with stress - this is used clinically to test corticotroph function following insulin challenge
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13
Q

What is the basic structure of the adrenal glands?

A
  • sit on top of kidney

- split into the adrenal cortex and medulla

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14
Q

What are the adrenal cortex hormones?

A
  • corticosteroids: glucocorticoids, mineralocorticoids
  • -> synthesised with P450 cytochrome enzymes
  • (weak) androgens
  • -> derived from cholesterol (synthesised from acetate)
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15
Q

Describe the histological zonation of the adrenal glands

A

Cortex split into 3 zones:
1. Zona glomerulosa
2. Zona fasciculata
3. Zona reticularis
(All 3 responsible for corticosteroid synthesis)
Medulla responsible for catecholamine synthesis

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16
Q

How is cholesterol imported into mitochondria?

A
  • by Steroidogenic acute regulatory (StAR) protein
  • transported from mitochondrial membrane into inner mitochondrial membrane
  • this is the RATE LIMITING STEP
17
Q

Describe the structure and regulation of StAR protein

A
  • contains a cholesterol transfer domain
  • produced in response to stimulation usually through a cAMP secondary messenger system
  • promoted by ACTH and LH
  • suppressed by alcohol
18
Q

How is pregnenolone formed?

A

cholesterol –> pregnenolone
- using cytochrome P450scc
(scc = side chain cleavage)
- occurs within inner membrane of mitochondria
- two hyrdoxylase reactions produce 20,22-dihydroxycholesterol
- final stage = cleavage of bond between carbon 20 and 22 to produce pregnenolone

19
Q

How is P450scc regulated?

A
  • requires electrons for function
  • works in a complex with 2 other proteins: adrenodoxin reductive and adrenodoxin (these provide initial electrons)
  • always active but dependent on supply of cholesterol
  • ACTH induces expression of all the genes in the complex
20
Q

What are glucocorticoids?

A
  • C21 steroids
    Examples:
  • cortisol (aka hydrocortisone)
  • corticosterone

*cortisol binds, cortisone does not, cortisone is converted by the body to cortisol

21
Q

Describe the biosynthesis of glucocorticoids

A

CYP11B1

  • metabolises precursors to make cortisol
  • requires different layers of enzymes
22
Q

How is cortisol transported in the blood?

A
  • 90%+ bound to plasma protein
  • -> transcortin (CBG) - 80+%
  • -> albumin - 10%
23
Q

Why is cortisol transported bound to plasma protein?

A
  • lipophilic = doesn’t like water therefore transporting cortisol in blood is difficult
  • transcortin = carrier protein for cortisol
  • in circulation, cortisol exists in 2 forms, bound and unbound
24
Q

How does bound cortisol become unbound?

A

Random equilibrium means carrier proteins randomly drop off molecules

25
Q

What can impact cortisol levels in the body?

A
  • emotion via limbic system
  • biochemical stressors
  • drive for diurnal rhythm
26
Q

How is ACTH generated?

A
  • produced from single gene = POMC
  • ACTH produced when POMC gets cleaved by enzymes
  • ACTH acts on adrenal but is also a prohormone
  • can be cleaved into a-MSH (regulates melanocytes) and CLIP (no known function)
27
Q

What are the effects of ACTH?

A
  • interacts with cell surface receptor (melanocortin 2 receptor) and uses secondary messengers as peptide receptor
  • cAMP activates secondary messenger
Immediate = increased cholesterol into mitochondria 
Subsequent = increased gene transcription of hydroxylases, increased LDL receptors 
Long-term = increased size and functional complexity of organelles, increase size and number of cells => HYPERPLASIA
28
Q

What effects do glucocorticoids have on metabolism?

A

CARBOHYDRATES

  • increased plasma glucose
  • increased hepatic gluconeogenesis
  • inhibits glucose entry into tissues
PROTEIN 
muscles 
- increase breakdown of protein --> amino acids 
--> wasting/ growth retardation 
liver 
- increase uptake of amino acids 
--> protein synthesis 
--> gluconeogenesis

FAT

  • increased metabolism of fatty acids from adipose tissue –> gluconeogenesis
  • redistribution to extremities
29
Q

What are the effects of glucocorticoids on bones?

A
  • decreased absorption of Ca2+
  • increased excretion
  • inhibition of osteoblasts –> osteoporosis
30
Q

What are the effects of glucocorticoids on the CNS and the immune system?

A

CNS: affects mood and cognition

Immune system:

  • decreased lymphocytes, eosinophils (disease fighting white blood cells)
  • increased neutrophils, RBCs and platelets
31
Q

What are the therapeutic actions of glucocorticoids?

A
  • Anti-inflammatory: potentially decrease leukocyte action - rheumatoid arthritis: potential proteolysis at site of damage
  • Anti-allergic: decreased histamine synthesis and release
  • Immunosuppression

NEUROSCIENCE 2 (32 decks)

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