Nuclear Receptors

Question 1

Types of receptors

Answer 1

Membrane (majority):
through transduction pathway – bind the drug and cause an effect

Ion channels:receptor linked to a channel=open or close
Local anesthetic – sodium channel blocker
Benzos – chloride channel enhancer

Nuclear or cytoplasmic:
most hormones work through these channels
– receptors are located in the cytoplasm
– hormone must go through the membrane
– after the drug binds, the complex goes into the nucleus and changes transcription in that cell = an increase/reduce production of proteins

Question 2

Nuclear Receptor General MOA

Answer 2

Nuclear receptors modulate protein synthesis either directly or indirectly by inhibiting or promoting DNA transcription of proteins

Question 3

Receptor Structure

Answer 3

Made up of 3 parts:
-C-terminal end – function is to bind the drug (4 ring structure)

zinc fingers or “sticky fingers” (contain 2 zinc molecules) – binds to the DNA or transcription factors
- Zinc fingers are covered by heat shock proteins (HSP) (no desire to bind)
– HSP fall off when C terminal binds a drug
–zinc fingers and become sticky and want to bind DNA or transcription factors.
–Once bound, N-terminal does its thing (drug/receptor complex goes to the nucleus and binds to the DNA)

N-End terminal – causes the DNA to change (increase or decrease in protein synthesis)
N-terminal either turns on or turns off the promoter region in DNA

Question 4

Direct action mechanism

Answer 4

Drug-receptor complex binds to DNA (RE/promoter region – response element or promoter) to inhibit or promote transcription

The direct mechanism requires two drug receptor complexes that bind to a response element to cause an action

Important: drug receptor binds DNA and it takes 2 drug-receptor complexes

Question 5

Indirect action mechanism

Answer 5

Drug-receptor complex binds to a transcription factor preventing it from binding to DNA. This inhibits the transcription of proteins.

The indirect mechanism requires only one drug-receptor complex to bind to transcription factor
The drug will not go into the nucleus

Important: Drug receptor complex does NOT go into nucleus, and only takes 1 complex

Question 6

Direct and indirect action mechanisms

Answer 6

Both change the action of DNA

Question 7

Glucocorticoid (steroid receptors)

Answer 7

GR 1 – binds mineralocorticoids (aldosterone) in kidney, colon, saliva glands, and hippocampus

GR 2 – binds glucocorticoids (anti-inflammatory steroids) everywhere

used to alleviate acne and psoriasis

Question 8

Retinoid receptors (bind retinoid drugs)

Answer 8

Retinoic acid receptor (RAR)

Subtypes – alpha, beta and gamma

Retinoid X receptor (RXR) no known subtypes

used to alleviate acne and psoriasis

Question 9

Vitamin D receptor

Answer 9

VDR

used to alleviate acne and psoriasis

Question 10

Dimerization

Answer 10

Direct action requires 2 drug receptor complexes for action
Combining of receptors = dimerization

Homo-dimer = A+A

Hetero-dimer = A+B

Glucocorticoids (steroids) only make homo-dimers
GR1+GR1 or GR2+GR2

Retinoid receptors make both homo-dimers and hetero-dimers
RAR+ RAR or RXR+RXR or
RAR+RXR

Vitamin D receptor only makes hetero-dimers
VDR+RAR or VDR+RXR

Question 11

Response elements or Promoter region

Answer 11

(Binding Sites)

GRE – Glucocorticoid Response Element

RARE - Retinoic Acid Response Element

TRE - Transcription Response Element

Bind to DNA in response elements (promoter regions)
GRE – where steroids bind on the DNA
RARE – where retinoids bind on the DNA
TRE – where transcription factors bind on the DNA

Question 12

Transcription Factors

Answer 12

Nuclear Factor Kappa B – NF-kb

Activator Protein 1 – AP1

Alter DNA transcription 
-bind to DNA at their TRE

Question 13

How it all works

Answer 13

Direct: In the case of steroids – Drug binds to a GR1 or GR2 (steroid receptors) When a homodimer of steroid-receptorcomplex binds to the GRE in DNA, steroids promote the production of anti-inflammatory proteins or inhibit the transcription of inflammatory proteins

Indirect: When steriods bind to a GR1 or GR2 and then that single complex binds uses its zinc fingers to bind to the transcription factors, prevents them from binding to the TRE on DNA

Transcription factors make inflammatory proteins – when you bind the drug/receptor complex to the TF, you prevent inflammatory proteins from being made

**Both direct and indirect action are occurring at the same time  alters transcription (1:35)