167. Mechanisms of Hormone Action

Question 1

Desensitized and downregulated by phosphorylation or by endocytosis

Answer 1

GPCRs

Question 2

Present as goiter and tachycardia

Elevated thyroid hormone and normal TSH level

Most common = inactivating mutation in thyroid hormone beta receptor

• beta receptor becomes more active
• other mutations exist

Answer 2

Resistance to thyroid hormone

Question 3

3 components:

1) Extracellular Ligand Binding domain
2) Single TM domain
3) Intracellular tyrosine kinase catalytic domain

Need to homo-dimerize to activate kinase domains that leads to phosphorylation of many downstream domains and proteins

Answer 3

Receptor tyrosine kinase

Question 4

Autosomal recessive

Laron Dwarfism

Insensitivity to GH

Reported resistances to diabetes and cancer

Answer 4

Growth Hormone receptor mutations

Question 5

These receptors act like other tyrosine kinases, but signaling occurs via associate tyrosine kinase associated proteins (Janus Kinase - JAKs)

25 known ligands

Important ones:

• Growth Hormone - needed for growth
• Prolactin - needed for reproduction/lactation
• Leptin - suppresses appetite

Answer 5

Cytokine Activated Receptors

Question 6

46XY, Genetically male
Phenotype - female

Androgen receptor mutated
Cells can’t sense testosterone
- thus, testosterone is converted to estrogen (reason why they look like females)

Answer 6

Complete androgen insensitivity syndrome

Question 7

Same structure as receptor tyrosine kinases except these receptors phosphorylate serine/threonine

Two types of receptors:

• Type I - 12 genes
• Type II - 5 genes

Type I and II interact to mediate signaling as dimers

Answer 7

Receptor Serine/Threonine Kinases

Question 8

Autosomal recessive
- inactivating mutations

Early-onset morbid obesity

Hyperphagia

Answer 8

Leptin receptor mutations

Question 9

Gain of function mutation of GPCRs

Autoantibodies made to TSH-Receptor
- increase sympathetic andrenergic activity and metabolic rate

Answer 9

Graves’ Disease

Question 10

100 different types exist

Most sequence/structural variation is in the extracellular domain

Examples of ligands:

• insulin
• epidermal growth factor
• platelet-derived growth factor

Answer 10

Receptor tyrosine kinases

Question 11

Rickets type 2
- hereditary vitamin D resistance

Presents as:

• Rickets
• Alopecia in most pts
• High levels of 1,25(OH)2VitaminD3
• Variable degrees of hypocalcemia
• Secondary hyperparathyroidism

Answer 11

Mutations in Vitamin D receptor

Question 12

Made by cleavage of PIP2 by phospholipase C in the non-classical Gq protein GPCR pathway

Ligand for ligand-gated ER bound calcium channels

Answer 12

IP3

Question 13

Stimulates and inhibit cAMP production by adenylate cyclase respectively

Classical pathway G proteins

Answer 13

Gs and Gi

Question 14

Nuclear receptor regulate ___ via:

1) ligand-dependent activation
2) ligand-dependent negative regulation

Answer 14

Gene transcription

Question 15

Example of a genetic defect that affects the tyrosine kinase receptor mechanism

Insulin receptor:

• impaired insulin binding or signaling via mutations in insulin receptor
• –> leads to severe insulin resistance

Most individuals die young (by age of 1yo)
- d/t inability to grow

Answer 15

Donohue syndrome (leprechaunism)

Question 16

Induces phospholipase C mediated cleavage of PIP2 to IP3 and DAG

(non-classical G protein)

Answer 16

Gq

Question 17

Often discovered at puberty d/t no menses in a “woman”

Other findings:

• absence of axillary and pubic hair in most cases
• No ovaries
• testes found intra-abdominally and/or in inguinal ring
• No meaningful spermatogenesis as sperm cells need testosterone for initiation
• Vagina often ends as blind pouch

Answer 17

Complete androgen insensitivity syndrome

Question 18

Loss of function of CaSR (calcium sensing receptor)

• autosomal dominant mutation
• GPCR mutation

Need to distinguish from primary hyperparathyroidism
- concentration of urine calcium will be high in patients with this disease

Low calcium in kidney, high calcium in blood

Answer 18

Familial Hypocalciuric Hypercalcemia

Question 19

Common features:

• small (less than 1000 daltons)
• lipophilic
• Not directly encoded by the genome, rather synthesized from cholesterol by enzymes or sourced exogenously

Answer 19

Ligands for nuclear receptors

Question 20

7 TM helices

Coupled intracellularly to heterotrimeric protein - G protein, consisting of the alpha, beta, and gamma subunits

Extracellular domain determines ligand specificity

Intracellular domain determines function via G protein specificity

Answer 20

GPCR

Question 21

Example of a GPCR disease d/t loss of function of the GPCR mechanism or the vasopressin 2 receptor

Mutation in vasopressin 2 receptor that concentrates urine
- aquaporins can’t get to cell membrane in these patients

Answer 21

Nephrogenic Diabetes Insipidus

Question 22

5-HT2 serotonergic receptors

Alpha-1 adrenergic receptor

Vasopressin receptors

Angiotensin II receptor Type 1

Answer 22

Membrane receptors that use Gq proteins

Question 23

Thyroid hormone 
Estrogen 
Testosterone 
Progesterone 
Aldosterone 
Cortisol 
1,25 - (OH)2 - Vit D3

Answer 23

Classic Nuclear hormones

Question 24

Gain of function mutations of GPCRs
- hyperfunctional and sporadic

Somatic mutations > autonomous

Hyperfunctioning thyroid nodules (toxic adenomas) leading to hyperthyroidism

Low TSH, high thyroid hormone levels

Answer 24

TSH-receptor mutations

Question 25

Main action steps:

1. Ligand binding
2. For most receptors: Dimerization to either homo- or heterodimers
3. Binding to Hormone Response Elements (HREs) = receptor specific DNA sequence close to the promotors of genes regulated by this particular receptor
4. Optional: binding of co-activators
5. Activation or repression of gene transcription

Answer 25

Nuclear receptor activity