Endocrine receptors and signalling pathways Flashcards
Lipid-Soluble Hormones
(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
Water-soluble Hormones
(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
ligand-gated ion channels
ionotropic receptors
hyperpolarisation or depolarisation –> cellular effects.
super fast
nicotinic ACh receptor, e.g.
G protein-coupled receptors
metabotropic
second messengers –> Ca2+ release, protein phosphorylation, and other stuff
e.g. muscarinic ACh receptor
kinase-linked receptors
–> protein phosphorylation–> gene transcription–> protein synthesis –> cellular effects
hours
cytokine receptors, e.g.
nuclear receptors
–> gene transcription–> protein synthesis–> cellular effects
e.g. estrogen receptor
Gas signaling pathway
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
Gai signaling pathway
Inhibition of cAMP production and PKA activity; Activation of K+ and inhibition of Ca2+ channels
α-adrenergic, somatostatin
Gaq signaling pathway
Phospholipase C, DAG, IP3, protein kinase C, voltage-gated Ca2+ channels
GnRH, TRH
Receptor Tyrosine Kinases (RTKs)
signaling pathway: MAP kinases, PI3-K, RSK
insulin, IGF-1, growth factor receptors (EGFR, PDGFR, VEGFR, etc.)
important in many cancers (oncogenic growth)
cytokine receptors
Lack intrinsic enzyme activity
JAK-STAT
GH, PRL
Serine Kinase Receptors
Smad proteins (signaling pathway)
TGF-beta, e.g.
Nuclear Receptors
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
nuclear receptor drug targets
Illnesses associated with dysfunctional nuclear receptor systems include inflammation, cancer, diabetes, cardiovascular disease, obesity, and reproductive disorders
NR Control of Gene Transcription
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
Hormone Regulatory Mechanisms
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
Growth hormone-releasinghormone (GHRH) (+)
Somatostatin (–)
Growth hormone(GH, somatotropin)
Liver, bone, muscle, kidney, and others
via Insulin-likegrowth factor-1 (IGF-1)
Thyrotropin-releasing hormone(TRH) (+)
Thyroid-stimulating hormone(TSH)
thyroxine, triiodothyronine,
Corticotropin-releasing hormone (CRH) (+)
Adrenocorticotropin (ACTH)
to adrenal cortex for cortisol
Gonadotropin-releasinghormone(GnRH) (+)2
Follicle-stimulating hormone (FSH)
Luteinizinghormone(LH)
target organ: gonads
estrogen, progesterone, testotsterone
Dopamine(–)
prolactin
growth hormone drug
somatropin
insulin-like growth factor-1 agonist
mecasermin
somatostatin analogs
octreotide, lanreotide
GH antagonists
pegvisomant
dopamine agonists
bromocriptine
cabergoline
vasopressin receptor agonists
vasopressin
despmopressin
vasopressin receptor antagonists
conivaptan
tolvaptan
Growth Hormone pharmacodynamics
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
Growth Hormone: Clinical Uses
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
Mecasermin
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
Growth Hormone Antagonists- 2 strategies
Reduce secretion of growth hormone
- Somatostatin analogs: octreotide, lanreotide
Block action of growth hormone at receptors
- Growth hormone receptor antagonist: pegvisomant
Somatostatin Analogs
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)
Pegvisomant
MOA: GH receptor antagonist
Inhibits binding of GH and prevents signal transduction
More effective than somatostatin analogs
Prolactin (PRL)
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
Bromocriptine & Cabergoline
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
Posterior Pituitary Hormones
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)
Vasopressin MOA, etc.
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
Vasopressin Antagonists MOA, etc.
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)
