Hormones and Receptors

Question 1

Define hormones

Answer 1

Signaling molecules that traffic information from one point to another through soluble medium

Question 2

What are the main classes of hormones?

Answer 2

1. Steroids
2. Monoamines
3. Peptides
4. Proteins
5. Eicosanoids

Question 3

Define endocrine, paracrine, autocrine and intracrine

Answer 3

• Endocrine: hormone produced in one tissue causes effect on target tissue at a distant location
• Paracrine: hormone acts locally, on a neighbouring cell
• Autocrine: hormone acts locally, on the secretory cell itself
• Intracrine: hormone acts on secretory cell without release from the producer cell

Question 4

List 4 differences between endocrine and nervous sytems

Answer 4

1. Nervous system is highly compartmentalized, endocrine system has distant targets
2. Nervous system sends message instantly, endocrine system is delayed
3. Nervous system has LOW ligand-receptor affinity, endocrine system has HIGH affinity
4. Nervous system has a small volume of distribution (ex. synapse), endocrine system is large

Question 5

Define endocrine glands

Answer 5

Ductless glandular structures that release hormone secretions

Question 6

How are hormone levels regulated?

Question 7

Explain the Scatchard equation

Answer 7

Knowledge of the concentration of bound and free ligand provides information about the ligand-receptor affinity and the total concentration of receptor.

Question 8

Define agonist and antagonist

Answer 8

• Agonist: ligand that triggers the effector mechanism and produces biologic effects
• Antagonist: bind the receptor but do not activate the effector mechanism

Question 9

What are the classifications of peptide hormone (and neurotransmitter) receptors?

Answer 9

1. 7 transmembrane domain (ex. beta adrenergic, PTH, LH, TSH, GRH, TRH, ACTH, MSH, glucagon, dopamin, a2 adrenergic, somatostatin)
2. Single transmembrane domain
   
   • Growth factor receptors - intrinsic tyrosine kinase activity (ex. insulin, IGF, EGF, PDGF)
   • Cytokine receptors - accessory protein with TK domain (ex. GH, prolactin, erythropoietin, CSF)
   • TGF beta receptor - serine/threonine kinase
   • Guanylyl cyclase-linked receptors (ex. natriuretic peptides)

Question 10

Where are the following receptors commonly found:

• Peptide (and neurotransmitter)
• Steroid

Answer 10

• Peptide/neurotransmitter: plasma membrane
• Steroid: nuclear receptor

Question 11

Draw a G protein coupled receptor

Answer 11

Question 12

G proteins are heterotrimers. The identity of a G protein is defined by its ______ subunit.

Answer 12

Alpha

Question 13

List the 4 subtypes of G proteins

Answer 13

1. G alpha s (ex. beta adrenergic, TSH, glucagon) – activate adenylyl cyclase
2. G alpha i (ex. alpha-2 adrenergic, muscarinic) – inhibit adenylyl cyclase
3. G alpha q (ex. alpha-1 adrenergic)
4. G beta/gamma

Question 14

Name 2 bacterial toxins that can modify G protein alpha subunits

Answer 14

1. Cholera toxin
2. Pertussis toxin

Question 15

Name 5 genetic conditions resulting from G protein coupled receptor mutations

Answer 15

TSH Receptor

• Inactivating: TSH resistance
• Activating: AD nonautoimmune hyperthyroidism, toxic adenomas

TRH Receptor

• Inactivating: Central hypothyroidism

LH Receptor

• Inactivating: Leydig cell hypoplasia (males), hypergonadotropic hypogonadism (females)
• Activating: testotoxicosis (males)

FSH Receptor

• Inactivating: AR hypergonadotropic ovarian dysgenesis or hypogonadism (females), impairment in spermatogenesis (males)

GnRH Receptor

• Inactivating: Isolated hypogonadotropic hypogonadism

GHRH Receptor

• Inactivating: Isolated GH deficiency

PTH Receptor

• Inactivating: Blomstrand’s chondrodysplasia (homozygous), enchodromatosis (heterozygous)
• Activating: Jansens metaphyseal chondrodysplasia

CaSR

• Inactivating: Familial benign hypocalciuric hypercalcemia (heterozygous), neonatal severe hyperparathyroidism (homozygous)
• Activating: AD hypocalcemic hypercalciuria

ACTH/Melanocortin-2 Receptor

• Inactivating: Familial glucocorticoid deficiency type 1

Vasopressin

• Inactivating: X linked nephrogenic DI

Question 16

Where are receptors for the following steroid hormones located:

• Glucocorticoid
• Mineralocorticoid
• Androgen
• Progesterone
• Estrogen
• Thyroid hormone
• Vitamin D

Answer 16

• Glucocorticoid, Mineralocorticoid, Androgen, Progesterone: cytoplasmic, multimeric complexes, HSP bound
• Estrogen: nuclear compartment, HSP bound
• Thyroid hormone, Vitamin D: bound to chromatin in nucleus

Question 17

List 3 genetic conditions resulting from mutations in steroid or thyroid hormone receptors

Answer 17

• Vitamin D-dependent rickets (type 2): vitamin D receptor
• Androgen insensitivity (complete or partial): androgen receptor
• Thyroid hormone resistance: thyroid receptor
• Pseudohypoaldosteronism: mineralocorticoid resistance
• Glucocorticoid resistance: rare, likely because it is so life-threatening

Question 18

List the steps of GH receptor signaling (cytokine receptor)

Answer 18

1. Two domains of single GH molecule bind two independent GH receptors, dimerization occurs
2. Janus kinase (JAK) 2 is activated, undergoes autophosphorylation
3. Tyrosine phosphorylates GH receptor and provides a docking site for signal transducer and activator of transcription (STAT)
4. STATs are phosphorylated, dissociate from GH receptor, migrate to nucleus and bind DNA regulatory elements
5. Transcription occurs (ex. of IGF1 gene)

Question 19

List the steps in thyroid hormone function

Answer 19

1. T3 and T4 circulate bound to thyroid binding proteins. Free hormones diffuse through cell membrane
2. In cytoplasm, T4 is converted to T3 by deiodinase
3. T3 moves to the nucleus and binds to thyroid receptor (TR) monomer
4. Heterodimerization with RXR (retinoid X receptor) on the TRE (thyroid response element), displacement of co-repressors and binding of co-activators
5. Gene transcription activation by TR-co-activator complex

Question 20

List the steps in testosterone function

Answer 20

1. Passive diffusion of testosterone into the cytoplasm and nucleus
2. Binding of testosterone to ligand-binding domain on androgen receptor
3. Homodimerization of receptor
4. Binding of homodimer’s DNA binding domain to hormone response element (HRE)
5. Transcriptional activation by activation function (AF-2) of ligand binding domain
6. Diffusion of co-repressors
7. Activation of co-activators –> DNA transcription
8. Translation of mRNA to protein, hormone effect at target cell

Question 21

Steroid hormone receptors like to form ____dimers, while thyroid hormone receptors like to form ____dimers

Answer 21

Steroid hormone receptors like to form HOMOdimers, while thyroid hormone receptors like to form HETEROdimers with RXR (also vitamin D receptor)

Question 22

Name 6 hormones each that act via:

1) Membrane receptors
2) Intracellular/nuclear receptors

Answer 22

Membrane receptors:

• G protein coupled: ACTH, TSH CRH, vasopressin, LH, FSH, GnRH, TRH, GHRH, somatostatin, glucagon, oxytocin, PTH
• Cytokine: GH, prolactin, leptin
• Tyrosine kinase: insulin, IGF1, fibroblast growth factor

Intracellular/nuclear receptors:

Glucocorticoids, mineralocorticoids, thyroid hormone, vitamin D, estrogen, androgens

Question 23

Name 4 hormones for which measurement by standard assays are influenced by binding proteins

Answer 23

1. Cortisol
2. Thyroid hormones (T3 and T4)
3. Testosterone
4. Estradiol
5. IGF1 & GH

Question 24

Name 2 genetic conditions resulting from GNAS1 mutatinos (G protein alpha subunit, NOT G protein coupled receptor)

Answer 24

• Inactivating:
  
  • Pseudohypoparathyroidism type 1 (Albright Hereditary Osteodystrophy)
  • Pseudopseudohypoparathyroidism
• Activating: McCune albright syndrome