Endocrinology and cell signalling Flashcards
What is Cushsings syndrome?
Excess glucocorticoids - cortisol
What disease will someone with Hypoadrenalism suffer from?
Addisons
Name 4 hormones which are synthesised in the Anterior Pituitary gland
Growth hormone Follicle stimulating hormone Leutinising hormone Thyroid stimulating hormone Adrenocorticotrophic hormone Prolactin
Give 5 functions of cortisol
Maintain muscle function Decrease bone function Decrease connective tissue Inhibit inflammatory and immune response Maintain cardiac output Facilitate maturation of foetus Increase glomerular filtration Modulate emotional tone
List 3 things which could cause excess hormone production
Neoplasm in endocrine gland
Ectopic production
Hyperplasia of endocrine tissue
List 4 things which could cause a deficit in hormone production
Trauma
Disease
Autoimmune attack of gland
Under development of gland
Give 2 examples of peptide hormones
Parathyroid
ACTH
How are steroid hormones synthesised?
Hydrolysis of esters or uptake of cholesterol
Cholesterol converted to pregnenalone by C P450 in mitochondria
Pregnenalone is processed in smooth ER
Then diffuses out of the cell
Which cells generally have autocrine signalling as a common feature?
Tumour cells
Production of growth hormones perpetuates proliferation
What 3 effector mechanisms can be used to change cell behaviour?
Alter gene transcription
Alter ion balance across membrane
Alter level of enzyme activity
Which residues does phosphorylation mostly occur on?
Serine and threonine
Describe the phototransduction pathway?
Photon binds to rhodopsin receptor
Transducin mediator
cGMP phosphodiesterase converts cGMP to GMP
Closes Na channels and changes membrane potential
In order for a molecule to diffuse across a membrane, what must occur?
Solute must dissolve in the hyrophobic core of the membrane
What are GLUT transporters?
Passive transporter
Glucose transported into cell and then converted to glucose 6 phosphate in order to maintain concentration gradient
What is an endocrine gland?
Gland which secretes hormones directly into the blood stream
What is an exocrine gland?
Gland which secretes chemicals via a duct
What tissues have endocrine function?
Heart
Gut
Adipocytes
Placenta
What are 3 types of hormones?
Polypeptides
Steroids
Modified amino acids
Describe steroid hormone synthesis
Hydrolysis of esters and cholesterol uptake
Conversion of cholesterol to pregnenalone in mitochondria
Processing of pregnenalone in smooth ER
Diffusion from the cell
Describe protein and peptide hormone synthesis
Gene transcription
Translation on rough ER
Post translational modification in Golgi
Packaging into secretory vesicles which are stored and ready for release when signalled
How is parathyroid hormone synthesised?
Peptide hormone
Pre-pro-PTH with signal, pro, biologically active and c terminal fragments
Cleaved twice to form active PTH
How is ACTH formed?
Peptide hormone
Formed as propriomelanocortin which is cleaved into ACTH, amino terminal fragment and B-lipotropin
Give an example of a tyrosine kinase receptor system
Insulin
What is the only example of a positive feedback loop in endocrinology?
LH surge in menstruation caused by oestrogen levels
Describe the anatomy of the thyroid gland
2 lateral lobes and an isthmus
In front of trachea
Large: 5cm long, 2-3cm deep, 3-4cm wide, 15-20g
What hormones does the thyroid gland make?
Basal metabolic rate: thyroxine (T4), tri-iodothyronine (T3)
Calcium homeostasis: calcitonin
What are T3 and T4 derived from?
Tyrosine
4 iodine molecules in T4
3 iodine molecules in T3
Describe the thyroid gland microstructure
Made of follicles: follicular cells containing colloid, parafollicular cells (c cells)
Follicular cells produce T3 and T4
Parafollicular cells produce calcitonin
What are the steps of thyroid hormone synthesis?
Thyroglobulin synthesis (from tyrosine) - colloid
Uptake and concentration of iodide (I-)
Oxidation of iodide to iodine (Thyroid peroxidase, luminal membrane of follicular cell)
Iodination of thyroglobulin to MIT and DIT mono-, di-iodotyrosine
Conjugation of 2 iodinated tyrosine molecules to form T4 or T3
Secretion
What does the thyroid gland do to iodide?
Concentrates it
Follicles actively accumulate iodine (iodide) from blood and secrete it into colloid
Describe iodide trapping by the thyroid gland
Iodide enters cell by a Na/iodide symporter located on basolateral side of follicle cell
What are dietary sources of iodide?
Seawater so sea food
Sea salt
Fruit and vegetables (depends on soil/imports)
Supplemented foods (salt, chocolate)
What is the most important nutritional deficiency? What is done to combat this in the UK?
Iodide
Most salt supplemented with iodine
What regulates thryoid hormone secretion?
Hypothalamic, pituitary, thryoid axis
Hypothalamus releases thyroid releasing hormone
Which stimulates anterior pituitary to release thyroid stimulating hormone
This stimulates the thyroid to release T3 and T4. Release of each factor has a negative feedback effect on release of those downstream
What is TSH (thyroid stimulating hormone)?
Released from anterior pituitary
Glycoprotein which stimulates follicles
Similar to FSH, LH (follicle stimulating hormone,luteinising hormone) FSH, LH and TSH: All have alpha and beta chains
Made independently
How does TSH increase thyroid hormone synthesis and secretion?
Receptor -> cAMP -> activates protein kinases -> phosphorylations at multiple sites to stimulate follicles to release thyroid hormones
Describe thyroid hormones in the circulation
Lipophilic so can’t readily dissolve in blood
Associated with proteins – 70% -thyroxin (thyroid) binding globulin (TBG), 30% bound to albumin
TBG has a higher affinity for T4
Only free T3/T4 can enter cell
Free hormones physiologically active
Which thyroid hormone can activate the thyroid receptor?
T4 has to be converted to T3 to bind to the T3R and have effect
Deiodinases interconvert T3/T4/rT3
Describe the types of Thyroid Hormone deiodinases
Peripheral tissue regulate T3 levels by increased or decreased deiodinases
Type 1 – cell surface of most cells, increase local T3
Type 2 – Intracellular raises T3 in CNS and pituitary
Type 3 - Removes iodine from T4 to make reverse T3(rT3). Especially placenta and CNS
What type of receptor is the thyroid hormone receptor?
Nuclear receptor
Leads to transcription and protein synthesis
What are the physiological actions of thyroid hormones?
Metabolism: all metabolic pathways, anabolic and catabolic, affects basal metabolic rate
Maturation and differentiation: bone/lungs/brain, CNS development
Neurological functions: synapse formation, myelinogenesis, neuronal outgrowth
Growth: Regulated by GH, but T3/T4 needed, skeletal
At what point of gestation does the thyroid gland start producing thyroid hormone?
12 weeks
What is Cretinism? And what test can be done for it?
Impaired physical and neurological development due to iodine deficiency during foetal or postnatal development
After 1st 2 years of life effects can’t be reversed screen in USA and UK
TSH in heel prick test
What are the effects of activation of the thyroid receptor?
Activity of cell membrane NaKATPase, mitochondrial enzymes
Leads to increased oxygen consumption and increased metabolic rate
In order to match increased oxygen consumption caused by T3, what needs to happen?
Increase ventilation (so increase respiration) Deliver O2 - increase heart rate, increase blood flow, increase myocardial activity so increase cardiac output O2 use needs substrates for oxidation: proteins/lipids/carbohydrate metabolism so increase food intake or mobilisation of stores
What will result from the increased metabolic rate seen with thyroid hormone receptor activation?
Increased CO2, ventilation Increased urea Increased renal function Decreased muscle mass Decreased adipose tissue Increased thermogenesis Leading to sweating, increased ventilation, surface blood flow
What symptoms might be seen in hyperthyroidism?
Palpatations, lose weight, increased respiration, anxiety, diarrhoea, heat tolerance, sweating, weight and muscle loss, increased appetite, nervous irritability, goitre
What symptoms might be seen in hypothyroidism?
Weight gain, decreased metabolic rate, lethargic/ slow, alopecia, goitre
What problems can be see with thyroid gland function?
Gland formation/function Iodine supply (deficiency) Signalling pathways (TSH, TRH) Congenital or acquired Thyroid hormone resistance (T3R defect)
What are the symptoms of hyperthyroidism called?
Thyrotoxicosis
What is Graves’ disease?
Auto-antibody (TSI) binds to TSH receptor. Causes hyperthyroidism
How can hyperthyroidism be diagnosed?
Measure serum TSH, free T3, free T4
Increased T3/T4
Increased TSH – fault in or above pituitary gland
Decreased TSH – thyroid gland problem (tumour/graves)
What is an obvious sign of Graves disease?
Protruding eyes - exophthalmos
What are symptoms of hypothyroidism called?
Myxoedema
What can cause hypothyroidism?
Hasimotos thyroiditis (auto-immune destruction) Iodine deficiency
How can hypothyroidism be diagnosed?
Measure Serum TSH, free T3, free T4
Decreased T3/T4
Increased TSH – usually
What is goitre?
Enlarged thyroid gland
What can cause goitre?
Iodine deficiency (low levels of T4): induces TSH secretion Graves disease (high levels of T4): autoimmune disease that produces thyroid stimulating immunoglobulin - acts as TSH Tumours (benign or cancer)
How do both low and high T4 induce a goitre?
Iodine deficiency leads to increased TSH stimulation and therefore gland growth
Graves’ disease results in thyroid stimulating immunoglobulin activating the gland and so leads to growth
What are treatments for thyroid problems?
Drugs (inhibit production/replace hormone)
Radioactive iodine (131I) (destroy gland)
Surgery
What are potential risks with thyroid surgery?
General surgery issues
Vocal cord nerve damage
Bleeding
Parathyroid gland damage
List five characteristics of membrane transporters
Integral membrane proteins Channels or carriers Specific (or selective) Regulated Passive or active
