Endocrine receptors and signalling pathways

Question 1

Lipid-Soluble Hormones

Answer 1

(Steroids, thyroid hormones)

Androgens, cortisol, estrogen, progesterone, thyroxine, vitamin D

use nuclear receptors

signaling mechanisms: Modulate gene transcription, and thus protein translation

time scale: hours to days

Question 2

Water-soluble Hormones

Answer 2

(peptides, proteins)

ACTH, CRH, FSH, GH, GHRH, GnRH, IGF, insulin, LH, PRL, SST, TRH, TSH

Transmembrane receptors (on the cell surface)

Second messengers modify protein phosphorylation, enzyme activity, etc.

Fast: seconds to minutes

Question 3

ligand-gated ion channels

Answer 3

ionotropic receptors

hyperpolarisation or depolarisation –> cellular effects.

super fast

nicotinic ACh receptor, e.g.

Question 4

G protein-coupled receptors

Answer 4

metabotropic

second messengers –> Ca2+ release, protein phosphorylation, and other stuff

e.g. muscarinic ACh receptor

Question 5

kinase-linked receptors

Answer 5

–> protein phosphorylation–> gene transcription–> protein synthesis –> cellular effects

hours
cytokine receptors, e.g.

Question 6

nuclear receptors

Answer 6

–> gene transcription–> protein synthesis–> cellular effects

e.g. estrogen receptor

Question 7

Gas signaling pathway

Answer 7

Stimulation of cAMP production and PKA activity; cAMP has different effects in a variety of tissue

ACTH, β-adrenergic, CRH, FSH, GHRH, Glucagon, LH, PTH, PTHrP, TSH

Question 8

Gai signaling pathway

Answer 8

Inhibition of cAMP production and PKA activity; Activation of K+ and inhibition of Ca2+ channels

α-adrenergic, somatostatin

Question 9

Gaq signaling pathway

Answer 9

Phospholipase C, DAG, IP3, protein kinase C, voltage-gated Ca2+ channels

GnRH, TRH

Question 10

Receptor Tyrosine Kinases (RTKs)

Answer 10

signaling pathway: MAP kinases, PI3-K, RSK

insulin, IGF-1, growth factor receptors (EGFR, PDGFR, VEGFR, etc.)

important in many cancers (oncogenic growth)

Question 11

cytokine receptors

Answer 11

Lack intrinsic enzyme activity

JAK-STAT

GH, PRL

Question 12

Serine Kinase Receptors

Answer 12

Smad proteins (signaling pathway)

TGF-beta, e.g.

Question 13

Nuclear Receptors

Answer 13

Nuclear receptors (NRs) regulate gene transcription 
Examples include receptors for sex hormones (e.g., estrogen, androgen, progesterone), cortisol, aldosterone, thyroid hormone, and other molecules such as retinoic acid and vitamin D
48 nuclear receptors in the human genome – almost all play a vital role in endocrine signaling and metabolic regulation

Question 14

nuclear receptor drug targets

Answer 14

Illnesses associated with dysfunctional nuclear receptor systems include inflammation, cancer, diabetes, cardiovascular disease, obesity, and reproductive disorders

Question 15

NR Control of Gene Transcription

Answer 15

Ligand-activated transcription factors
The ligand-receptor complex is unstable and releases the chaperone, Hsp90
Dimerization permits nuclear entry, binding to specific DNA sequences (e.g., glucocorticoid response elements, GREs), and regulation of transcription
Some steroid-receptor complexes regulate transcription indirectly by modulating the action of other transcription factors (e.g., NF-κB)
Regulatory factors facilitate (coactivators) or inhibit (corepressors) the hormone response

Question 16

Hormone Regulatory Mechanisms

Answer 16

Positive feed-forward regulation
- Examples: GHRH, CRH, TRH, GnRH

Direct negative regulation
- Examples: somatostatin, dopamine

Negative feedback loops
- Examples: GH, sex hormones, cortisol

CNS input from other brain regions

Question 17

Growth hormone-releasinghormone (GHRH) (+)

Somatostatin (–)

Answer 17

Growth hormone(GH, somatotropin)

Liver, bone, muscle, kidney, and others

via Insulin-likegrowth factor-1 (IGF-1)

Question 18

Thyrotropin-releasing hormone(TRH) (+)

Answer 18

Thyroid-stimulating hormone(TSH)

thyroxine, triiodothyronine,

Question 19

Corticotropin-releasing hormone (CRH) (+)

Answer 19

Adrenocorticotropin (ACTH)

to adrenal cortex for cortisol

Question 20

Gonadotropin-releasinghormone(GnRH) (+)2

Answer 20

Follicle-stimulating hormone (FSH)
Luteinizinghormone(LH)

target organ: gonads

estrogen, progesterone, testotsterone

Question 21

Dopamine(–)

Answer 21

prolactin

Question 22

growth hormone drug

Answer 22

somatropin

Question 23

insulin-like growth factor-1 agonist

Answer 23

mecasermin

Question 24

somatostatin analogs

Answer 24

octreotide, lanreotide

Question 25

GH antagonists

Answer 25

pegvisomant

Question 26

dopamine agonists

Answer 26

bromocriptine

cabergoline

Question 27

vasopressin receptor agonists

Answer 27

vasopressin

despmopressin

Question 28

vasopressin receptor antagonists

Answer 28

conivaptan

tolvaptan

Question 29

Growth Hormone pharmacodynamics

Answer 29

Required during childhood and adolescence
Somatropin is recombinant human GH

Pharmacodynamics
Growth promoting effects are mediated through an increase in IGF-1 production
Stimulates longitudinal bone growth until the epiphyses close
Anabolic effects in myocytes; catabolic effects in adipocytes
Mixed effects on carbohydrate metabolism

Well tolerated overall

Question 30

Growth Hormone: Clinical Uses

Answer 30

GH deficiency
Due to damage to the pituitary or hypothalamus or genetic issue

Pediatric patients with short stature
Prader-Willi syndrome, Turner syndrome, Noonan syndrome, and idiopathic short stature

Other uses
Chronic wasting in patients with AIDS
Short bowel syndrome dependent on total parenteral nutrition
Banned by the Olympic Committee, professional sports
rBovine GH used in cattle to increase milk production; linked to bovine mastitis, which may increase antibiotic use and result in greater antibiotic residues in milk and meat

Question 31

Mecasermin

Answer 31

Recombinant human IGF-1 (rhIGF-1)
Mecasermin rinfabate: mixture of rhIGF-1 and rhIGF-binding protein-3 (IGFBP-3), which extends the half-life

Clinical Uses

• IGF-1 deficiency not responsive to rhGH therapy
• Children with GH gene deletions or who have developed neutralizing antibodies

Most common adverse effect is hypoglycemia

Question 32

Growth Hormone Antagonists- 2 strategies

Answer 32

Reduce secretion of growth hormone
- Somatostatin analogs: octreotide, lanreotide

Block action of growth hormone at receptors
- Growth hormone receptor antagonist: pegvisomant

Question 33

Somatostatin Analogs

Answer 33

Somatostatin (SST) inhibits the release of GH (as well as glucagon, insulin, gastrin, other hormones)
Exogenous somatostatin has a very short duration of action (1-3 minute half-life)
Recombinant SST analogs: octreotide, lanreotide
More potent than somatostatin in inhibiting GH and insulin secretion
Used in the treatment of anterior pituitary adenomas that secrete GH (acromegaly, gigantism)
Adverse effects include nausea, vomiting, GI (steatorrhea, gallstones) and cardiac effects (sinus bradycardia, conduction disturbances)

Question 34

Pegvisomant

Answer 34

MOA: GH receptor antagonist

Inhibits binding of GH and prevents signal transduction

More effective than somatostatin analogs

Question 35

Prolactin (PRL)

Answer 35

Direct action in target tissues through JAK/STAT receptors

No preparations are available for use in prolactin-deficient patients

Dopamine agonists are used to treat hyperprolactinemia

Question 36

Bromocriptine & Cabergoline

Answer 36

MOA: Dopamine D2 receptor agonists (coupled to Gαi/o, which inhibits adenylyl cyclase and decreases cAMP)
- Dopamine D2 receptors decrease prolactin secretion

Clinical Use: hyperprolactinemia (also acromegaly, Parkinson disease)
- Shrink pituitary PRL-secreting tumors, lower circulating PRL levels, and restore ovulation in 70% of women with microadenomas and 30% of women with macroadenomas

Adverse Effects

• Nausea, headache, light-headedness, orthostatic hypotension, fatigue are most common adverse effects
• Psychiatric manifestations are rare, but can take months to resolve

Question 37

Posterior Pituitary Hormones

Answer 37

Synthesized in cell bodies of hypothalamic neurons that project to posterior pituitary (no portal system)

No positive feed-forward regulation

Act directly on target tissues

Vasopressin (ADH)

Question 38

Vasopressin MOA, etc.

Answer 38

Vasopressin (antidiuretic hormone, ADH)

• Peptide hormone released in response to rising plasma tonicity or failing blood pressure; antidiuretic and vasopressor properties
• MOA: agonist at vasopressin (V1 and V2) receptors (GPCRs)
• Clinical Use: pituitary diabetes insipidus, hemophilia A, von Willebrand disease

Desmopressin has a longer half-life and is selective for V2 receptors

Question 39

Vasopressin Antagonists MOA, etc.

Answer 39

Conivaptan and tolvaptan

MOA: V2 receptors antagonists
Promotes the excretion of free water (without loss of serum electrolytes) resulting in net fluid loss
Increases urine output, decreases urine osmolality, and restores normal serum Na+ levels

Clinical Use: treatment of clinically significant hypervolemic or euvolemic hyponatremia (associated with heart failure, cirrhosis, or SIADH)