Receptors Flashcards
Drugs bind to receptors through formation of _________, _______ and _________ bonding,
Binding of the drug results in the activation or inhibition of a _______ ______________ pathway that involves receptor/drug-dependent set of cellular signals.
Hydrophobic; ionic; hydrogen (non-covalent)
Signal transduction
What is the result of non-covalent reactions being reversible?
Drugs dissociate from their receptors as their concentration in the plasma decreases.
Match the following terms to their definitions:
1) Affinity
2) Law of mass action
3) KD
A) the ratio of a drug receptor dissociation k2 and association k1 rate (k2/k1)
B) tendency of a drug to combine with its receptor
C) the numbers of receptors occupied by a drug depends on the concentration of the drug
Affinity: tendency of a drug to combine with its receptor
Law of mass action: the numbers of receptors occupied by a drug depends on the concentration of the drug
KD: the ratio of a drug receptor dissociation k2 and association k1 rate (k2/k1)
The lower the Kd, the ______ the affinity.
This occurs if the association rate (k1) constant is much ______ than the dissociation rate (k2).
higher; greater
(T/F) When a drug binds to a receptor, it will always activate the receptor.
False! Binding of a drug does not mean it’s activating the receptor, it can deactivate the receptor (antagonism).
AR* means:
activated drug receptor complex
How are most receptors classified? What are two families of receptors?
Receptors are classified based on their PRIMARY AMINO ACID SEQUENCE.
There are 1) intracellular receptors (nuclear receptors) and there are 2) membrane receptors (tyrosine kinases, g-protein linked, and ion channels).
Nuclear receptors are ligand activated _________ ______ that activate ______ synthesis.
Transcription factors; mRNA synthesis
*TF meaning it binds to the DNA
Match the different types of regions of a nuclear receptor to their definitions:
1) Variable
2) DNA Binding Domain (DBD)
3) Hinge
4) Ligand Binding Domain (LBD)
A) important for NUCLEAR LOCALIZATION. aka D site.
B) at the C-terminus. Composes of AF-2 site. aka E/F site.
C) contains Zn2+ fingers. aka C site.
D) at the N-terminus and contains AF-1 site. aka A/B site.
Variable: at the N-terminus and contains AF-1 site. aka A/B site.
DNA Binding Domain: contains Zn2+ fingers. aka C site.
Hinge: important for NUCLEAR LOCALIZATION. aka D site.
Ligand Binding Domain: at the C-terminus. Composes of AF-2 site activates transcription). aka E/F site.
Match the different types of regions of a nuclear receptor to their definitions:
1) Variable
2) DNA Binding Domain (DBD)
3) Hinge
4) Ligand Binding Domain (LBD)
A) 70 aa and HIGHLY CONSERVED
B) 200-250aa and MODERATELY CONSERVED
C) 50-500aa and VARIABLE
D) 45aa
Variable: 50-500aa and VARIABLE
DNA Binding Domain (DBD): 70 aa and HIGHLY CONSERVED
Hinge: 45aa
Ligand Binding Domain (LBD): 200-250aa and MODERATELY CONSERVED
Which domain of a nuclear receptor is the most important for pharmacology?
Ligand binding domain
(T/F) Receptor protein homologies reflect function and diversity of ligands. For example, steroid receptors are more homologous than non-steroids are to them.
True!
How do nuclear receptors activate specific genes?
They recognize specific sequences of DNA called HORMONE RESPONSE ELEMENTS (HRE), which are a class of “promoter enhancers.”
There are two identical/similar parts to the HRE called “HALF SITE MOTIFS” that each bind to one nuclear receptor (bind as dimers).
When the receptors bind, the promoter is activated leading to gene expression.
*this gives them specificity
While steroid receptors bind to DNA as ________, non-steroid receptors bind as _________ (oftern RXR).
Homodimers; heterodimers
Give examples of steroid receptors and non-steroid receptors.
Steroid receptors; glucocorticoid, mineralocorticoid, progesterone, androgen, estrogen
Others: T3R (thyroid), RAR (retinoic acid), VD3R (vitamin D3) and PPAR.
The two Zn fingers of a nuclear receptor contains four ________ in the base to coordinate a zinc ion. Thus, they are very _______!
Cysteines; stable
*one nuclear receptor has 2 zinc fingers; one has the P box, the other has the D box. a dimer has 4 zinc fingers!
The two Zn fingers of one nuclear receptor contain a P box and D box, where the P box is close to the ___-terminus, and the D box is close to the ___-terminus.
P box is responsible for:
D box is responsible for:
C, N
Recognizing the primary nucleotide sequence and binding to it.
Spacing of the half-site motif (of the two receptors on the DNA; does not contact the DNA).
(T/F) The P and D box are responsible for the ability of the receptors to specifically bind to certain gene enhancers to activate transcription of downstream genes.
True!
On the basis of the primary nucleotide recognition sequence, nuclear receptors can be divided into two families:
1) glucocorticoid-R family
2) estrogen/thyroid Hormone-R family
(T/F) The amino acid sequence of the P and the D box among nuclear receptors are highly homologous.
False!
The amino acid of the P box is almost identical to all receptors, while the amino acid sequence is different in all receptors for the D box.
The spacing of half-sites (caused by the D box) dictates which HREs are recognized (selectivity).
How do the D boxes determine the length of the spacing of the half site motifs?
D boxes of the dimers (1 d box in one monomer) can attract or repel one another.
If they attract, there are less nucleotides (~3) between the two half site motifs. If they repel, there are more nucleotides.
(T/F) The half sites of a dimer are palindromic sequences.
True!
What is the consensus DNA sequences for enhancers (HRE) which bind and are activated by the ER/TR family?
They are composed of a half-site motif; A G G T C A as a repeated sequence.
ex: AGGTCAXXXAGGTCA
While Vitamin D3’s half site motifs are separated by 3 nucleotides (direct repeat 3), the thyroid is separated by ____ nucleotides (direct repeat __), and the retinoic acid is separated by ____ nucleotides (direct repeat __)
4; 5
DNA is wound around ______ proteins in a condensed state and the DNA-histone interaction must be __________ for transcription to occur.
histone; loosened
*allows TFs to gain access to DNA
(T/F) The nucleosome consists of an octamer of four histones (two copies each of H2A, H2B, H3 and H4).
True!
What is a co-repressor and co-activator complex?
Give an example of each and describe how it works.
Co-repressor complex keeps the gene silent when there is no ligand bound.
HISTONE DEACETYLASE is an example of a co-repressor complex. It removes the negative acetyl groups, maintaining a positive charge on histones, attracting the negative DNA, causing it to be tightly wound.
Co-activator complex activates the gene when there is a ligand bound.
HISTONE ACETYLASE is an example of a co-activator complex. It adds negative acetyl groups on histones, loosening the DNA.
What does histone acetylation accomplish?
1) acetylation neutralizes the positive charge on histone tail to “loosen” the interaction between DNA and the histone
2) acetylation PATTERNS control the binding of non-histone proteins (RNA pol complex) to the chromatin fiber
(T/F) There are only synthetic ligand for nuclear receptors.
False! There are NATURAL and SYNTHETIC ligands.
The thyroid hormone is a critical hormone in _________; it controls _______ and _______ maturation.
It also cooperates with _______ nervous system by increasing ____________ receptors.
Most active hormone is ____ derived from _____ by _____________ in thyroid gland and in ______ and ______ tissues.
development; growth; sexual
sympathetic; adrenergic (adrenaline)
T3; T4; 5’-deiodinase; liver; muscle
What are the two preparations of the thyroid hormone?
Which one is given when there is a deficit in 5’-deiodinase?
1) Levothyroxine (T4)
2) Liothyronine (T3)
Liothryonine is given.
What does excess thyroid lead to?
Thyroid hormone controls metabolism:
1) Increases CARBOHYDRATE METABOLISM
2) Increases FAT METABOLISM (lipids are mobilized from the fat tissue)
3) DECREASES CHOLESTEROL, PHOSPHOLIPIDS and TRIGYCERIDES in the blood
4) Increases in enzymes requiring vitamins as coenzymes so INCREASED NEED FOR VITAMINS
5) BASAL METABOLIC RATE: increases metabolism in most cells of the body - TH can occasionally increase the basal metabolic rate to as much as 60-100% above normal
6) Decreases the BODY WEIGHT but increases the appetite
7) INCREASED heart rate
While people who have deficits in thyroid hormone are _____, people who have hyperthyroid are _____.
fat; thin
Thyroid deficiency can be due to:
What is it associated with? How?
Autoimmune (enzymes can attack glands and enzymes that make the TH) and iodide deficiency (leads to decrease in TH).
It is associated with GOITER.
How goiter is formed:
In the absence of TH, HYPOTHALAMUS becomes activated (T4 and T3 are negative regulators of hypothalamus).
Hypothalamus releases lots of Thyroid Releasing Hormone (TRH), which activates the PITUITARY.
Pituitary makes Thyroid Stimulating Hormone (TSH), which releases T4 and T3.
If the thyroid is functioning normally, T4 and T3 signal hypothalamus to stop making TRH. If it’s not functioning properly (maybe due to iodine deficiency), hypothalamus continues to release TRH, which leads to an increased amount of T3 and T4 production, resulting in a goiter.
Briefly answer these questions regarding estrogen:
1) What is the active form?
2) What is its role in development?
3) What is its role in reproduction?
4) What are its preparations?
5) What are its indications?
1) β-estradiol
2) Promote formation of fallopian tubes, uterus, and female secondary sexual characteristics.
3) Essential role in menstrual cycle/ovulation in both follicular and luteal phases
4) It is derived from pregnant horses. There can be conjugated equine estrogens (suphate esters of Estrone and equilin), and Ethinyl estradiol (synthetic)
5) Hormone replacement therapy (HRT) and treatment of infertility.
Contraceptives are estrogens in combination with __________.
Yasim/Yaz are a type of contraceptive that contain ________ which has ___________ and __________ activities. However, they increase the risk of ______ ______ due to reduced blood volume.
Progestins (synthetic mimic of progesterone)
Drospirinone; antimineralcorticoid*; antiandrogenic; blood clots (more than normal)
*antimineralcorticoid is a diuretic, which decreases the swelling caused by the contraceptives.
What is the function of testosterone in development and in reproduction?
In development: promotes male secondary sexual characteristics
In reproduction: necessary for sperm production
*testosterone binds to androgen receptors
What are the side effects of contraceptives with estrogen? Why?
What is a safer alternative?
Side effects: 1) Increased risk (0.09%) of THROMBOSIS, 2) may promote growth of BREAST CANCERS (esp post menopause)
E2-ER ACTIVATES the transcription of the PROCOAGULANT factors; II, VII, IX, X, XII, XIII and fibrinogen and INHIBITS the transcription of natural ANTICOAGULANT protein S and antithrombin.
Safer alternative is a PROGESTIN ONLY contraceptive.
What does SERMs stand for? What are they used for? Give two examples.
Selective Estrogen Receptor Modulators
They are used in the treatment of ER (+) breast cancer.
Tamoxifen and Raloxifene are SERMS.
How do SERMs cause proliferation in some cell types (uterus) and inhibit proliferation in other types of cell (breast cancer cell)?
What is the best case scenario for a SERM drug?
SERMs elicit different effects depending on several factors in different tissues and on different gene enhancers (response elements).
Different tissues have different TFs!
Best case scenario: AGONISM in bone (prevents osteoporosis in post menopause women) and CV system and ANTAGONISM in uterus and breast.
