174. Mechanisms of Hormone Action

Question 1

Nuclear Receptors

• what are the typical ligands?
• what are the action steps?
• how are they further regulated?

Answer 1

Ligands: small, lipophilic, not directly encoded by genome (synthesized by enzymes from precursors) [T3/T4, E, P, T, aldo, cortisol, active vit D]

1. Ligand Binding
2. Most Receptors then dimerize to homo/hetero dimers
3. Bind to HRE (receptor binding site specific DNA sequence for receptor, close to promoter region of specific genes)
4. Optional: bind co-activators/co-repressors
5. Activation/Repression of gene transcription (most activate)

Regulate via ligand levels, receptor levels, presence of co-activators and co-repressors
Co-activator: binds ligand receptor dimer on HRE: enhances fx of ligand-receptor and increases gene transcription
Co-repressor: binds receptor dimer w/o ligand on HRE to decrease transcription until ligand binds
allows finer regulation (100 fold control) of transcription

Question 2

Thyroid Hormone Resistance

• labs
• etiology
• sx

Answer 2

labs: high t3/t4, normal TSH
eti: inactivation mutation in THBR (thyroid hormone beta receptor)
THBR: responsible for regulating negative feedback (in liver, ear)
THAR: in brain, bone, heart (A + B in skeletal muscle)

Sx: goiter/enlarged thyroid - making more T3/T4
high BMR = high T3/T4 binding THAR in brain
tachycardia = high T3/T4 binding THAR in heart
accelerated bone loss = high T3/T4 binding THAR in bone
insomnia, restlessness, developmental delay = THAR in brain
HEARING LOSS = LOW THBR activity

Question 3

Complete Androgen Insensitivity Syndrome

• cause
• sx

Answer 3

Cause: 46XY = genetically male but female phenotype due to mutated androgen receptor, cells cannot sense T, T converted to E
Dx: at puberty, no menses
sx: no menses, no ovaries (tests form intraabdominal or inguinal), absence of axillary/pubic hair, no spermatogenesis, vagina ends as blind pouch (no internal female genitalia)
spectrum of phenotypes due to partial to complete insensitivity

Question 4

Hereditary Vitamin D Resistance (Rickets Type 2)

• cause
• other features of vit D resistance

Answer 4

Cause: inactivating mutation in vit D receptor, cannot be sensed by bone

Vit D Resistance: Ricket’s, Alopecia (vit D in hair development), variable degrees of hypocalcemia, secondary hyperparathyroidism (low Ca causes high PTH)

Question 5

Receptor Tyrosine Kinase

• components
• example
• action steps
• Donohue Syndrome (leprechaunism)

Answer 5

Parts: EC ligand-binding domain, single transmembrane domain, IC tyrosine kinase catalytic domain

ex: Insulin
1. ligand binds (ins)
2. Receptor dimerization (homo/heterodimer)
3. IC tyrosine kinase cross-phosphorylation
4. Phosphorylation of downstream proteins
5. GLUT4 translocation to membrane/downstream signaling events

DS: mutation in ins receptor - impaired ins binding/signaling
severe ins resistance: most die young (no ins in utero = organ underdevelopment and no growth in 1st year)

Question 6

Receptor Serine/Threonine Kinases

• structure
• types
• ex

Ligand Gated Ion Channel
- structure

Answer 6

RS/TK’s: same as RTKs but phosphorylate Ser/Thr
Type 1: 12 genes
Type 2: 5 genes
Type 1 and Type 2 interact as heterodimers
Ex: TGF-beta

LG IC: specific to ion in response to ligand binding (Na, Ca, K)

Question 7

Cytokine Activated Receptors

• structure
• ex
• GH receptor mutations
• Leptin receptor mutations

Answer 7

like RTKs but signaling via assoc tyrosine kinase assoc proteins (JAK STAT)
ex: GH, PRL, Leptin

GH Receptor mutations: AR (both alleles dysfx) = Laron Dwarfism (no GH effect) - insensitive to GH, resistance to DM and cancer

Leptin Receptor mutations: AR early-onset morbid obesity and hyperphagia

Question 8

GPCRs

• structure
• pathways
• regulation
• Nephrogenic DI
• Familial Hypocalciuric Hypercalcemia
• TSH Receptor Gain of Fx mutations
• Grave’s Disease

Answer 8

7 transmembrane helices coupled to IC heterotrimeric G protein
EC domain: ligand specificity
IC domain: fx via G-protein specificity
Gs/Gi path: stim/inhibit cAMP production by adenylate cyclase
Gq: induce PLC cleavage of PIP2 to IP3 and DAG (ligands for ER bound Ca channels, Ser/Thr Kinase receptor)
Produce 2nd msgrs!
Regulation: downregulated by phosphorylation (BARK activating beta-arrestin - activated by Gs) or endocytosis of receptor

Nephrogenic DI: loss of fx of AVP-2 receptor mutation: cannot move AQP2 to apical lumen, cannot conc urine, no response to synthetic ADH

FHypoCaU HyperCa: loss of fx mutation in CaSR on pth and kidney (AD), cause slightly high serum Ca, very high PTH, LOW CA IN URINE (usually subclinical, no tx needed)

TSH Receptor Gain of Fx: sporadic hyperfunctional somatic mutations lead to hyperthyroidism

Graves’ Disease: activating antibodies to TSH receptor = hyperthyroidism = low TSH, high T3/T4
sx: bulging eyes, tachycardia, goiter, tremor, high BMR