Transport and regulation Flashcards
Why is regulation of hormones necessary?
Effective action at the correct tissue (spatial regulation), at the correct time (temporal regulation)
To avoid unwanted side effects
How are peptide hormones transported in the blood?
eg. insulin, TSH, CRH, PTH
Water soluble
Hydrophilic
Dissolve in the plasma
How are steroid hormones transported in the blood?
eg. estradiol, progesterone, vitamin D
Not water soluble
Lipophilic
95-99% bound to plasma carrier proteins aka hormone binding proteins
How are amino-acid derived hormones transported in the blood?
eg. thyroid hormones, melatonin, adrenaline
Not water soluble
Lipophilic
Hormone binding proteins
What do oestradiol and testosterone bind to?
Sex hormone binding globulin
What do glucocorticoids bind to?
Corticosteroid binding globulin
What does vitamin D bind to?
Vitamin D binding globulin
What do thyroid hormones bind to?
Thyroid binding globulin and transthyretin
What is the non-selective binding protein?
Albumin
What proportion of cortisol, aldosterone and progesterone bind to albumin?
25%
47%
80%
What are the roles of hormone binding proteins?
Maintain a constant free hormone level
Maintain a large pool of hormone outside the endocrine gland
Safeguard the body from abrupt hormone fluctuations
Facilitate uniform cellular distribution
Allow site-specific delivery
Which hormones bind which receptors?
Peptide - cell surface receptors
Steroid and thyroid - intracellular receptors
What is the free hormone hypothesis?
Steroids and thyroid hormones reach their intracellular targets by passive diffusion
Hormones bound to proteins are inactive
There is an equilibrium between the free and protein bound form of the hormone
Describe steroid hormone uptake
Existence of cell surface binding sites for hormone binding proteins
Multiple roles: receptor for transmembrane signalling, local sequestration, mediate cellular uptake
What is megalin?
A receptor for the uptake of carrier bound vitamin D
Member of LDL receptor family
Expressed on apical surface of absorptive epithelia
Works alongside cubulin
KO = rickets
Shown in vitro to have many ligands
Prevents urinary loss of many hormones
Also binds SHBG (specifically to deliver DHT)
Can be blocked by receptor-associated protein
KO mice = closed vagina cavity and testicular maldescent
Needed for sexual maturation
What are the implications of binding globulins?
Not only free hormones are biologically relevant
Drugs that affect BP can impact endocrine function
What is vitamin D bound to?
90% to vitamin D BP
10% to albumin
0.1% is free
Albumin binding is weaker but the amount of albumin is 100x that of vitamin D BP
Free vitamin D correlates to bone mineral density
Describe polymorphisms in vitamin D BP
SNP change the affinity for vitamin D Different between black and white Variants Gc1F and GC1S Total vitamin D lower in blacks, vitamin D binding protein also lower Free vitamin D is comparable
How are thyroid hormones transported?
Monocarboxylate: MCT8 and MCT10 System L amino acid: LAT1 and LAT2 Organic anion polypeptide: OATP1C1, OATP1A2, OATP1A4 Facilitated diffusion Different distributions around the body
What are the affinities for T3 and T4?
MCT8 for T3
MC10 for T4
What is an example of microvillus membrane vesicles?
The placenta (synctiotrophoblasts) express a lot of TH receptors on the apical surface to take TH from the maternal blood
Describe mutations in MCT8
Located on X chromosome
Male patients with inherited defective form have altered serum thyroid hormone levels
Low T4 and elevated T3
Causes Allan-Herndon-Dudley syndrome
What is Allan-Herndon-Dudley syndrome?
Global neurodevelopment delay Absence of speech development Severe axial hypotonia Muscle hypoplasia Spastic quadriplegia 50+ families globally MCT8 is essential in neuron function
