Endocrinology first 3 lectures Flashcards
What are the characteristics of the hormone super families?
Peptides- stored for a day, secreted via exocytosis, lasts for mins-hours, works for mins-hours Steroids- stored for mins-hours, secreted by diffusion, lasts for hours, works for hours-day Thyroid hormones- stored for weeks, secreted by proteolysis, last for days, work for a day Catecholamines- stored for a day, secreted by exocytosis, last for sec-mins, work for seconds
Describe peptide hormones
Water soluble Largest in number Normally proteolytic ally cleaved to form the active hormone Stored in vesicles- for immediate release Made as preprohormones with a signal peptide and ‘inactive’ fragment.
Peptide hormones cant pass through the cell membrane and therefore bind to receptors on the cell surface.
Desribe protein synthesis
1) Messenger RNA on the ribsome of the ER binds amino acids into a peptide chain called preprohormone. The chain is directed to the ER lumen by the signal sequence of amino acids.
2) Enzymes in the ER chop off the signal sequence, leaving a prohormone, which travels to the golgi apparatus.
3) Secretory veiscles containing enzymes and prohormone are bud off the golgi. The enzymes chop the prohormone (containing an inactive fragment which silences the hormone) into one or more active peptides plus additional peptide fragments.
4) The secretory vesicle releases its contents by exocytosisinto the extracellular space.
5) The hormone moves into the ciculation for transport to its target.
Describe amino acid derivatives as hormones
Thyroid hormones from tyrosine in the thyroid gland.
T4 contains 4 iodine residues – only known need for iodine in the diet - metabolised to more active T3 (TR and splice variants)
Thyroid hormones are stored until they are needed, to allow for release upon stimulation.
Thyroid hormones are involved in metabolism and basal metabolic rate
Describe steroid hormones
Lipophilic- easily pass through the plasma membrane Includes sex hormones, glucocorticoids, thyroid hormone and vitamin D Not stored- produced on demand
Produced in adrenal cortex, corpus luteum and ovaries in women and testes in men
Synthesis starts from cholesterol (transported into mitochondria by StAR)➡️ pregnenolone by P450cc through 2 hydroxylase and one cleavage reaction
List the endocrine glands
Hypothalamus Pituitary Thyroid Parathyroid a Adrenals Pancreas Ovary Testes (Heart, intestines, skin, liver, kidney)
What is a hormone receptor?
Bind the hormone specifically
Be able to detect it and high enough affinity in blood amount related molecules
The receptor must be only on specific tissues?
Must be saturable
Reversible
Must mediate some biological response
Work through either either tyrosine kinases or G-proteins
Describe intrinsic tyrosine kinase activity
An enzyme that has the intrinsic ability to transfer a phosphate group from ATP to a tyrosine residue (tyrosine kinase for adding/phosphotase for removing phosphate), The phosphorylation causes a confomation change. Eg. Epidermal growth factor (EGF) receptor 1-4, ligand induced dimerisation, signal transduction processes- Eg. Dimerization➡ transphosphorylation (alter conformation)➡ GRB binds➡ SOS binds➡ Ras activated(+GTP GDP makes it inactive) Insulin receptor- PI 3-kinase (PI 3-kinase is attraced by phosphorylation which sends 2nd messenger to active transcrpition factors)
Describe recruited tyrosine kinase activity
When the receptor is dimerised it recruits JAK-STAT. Ligand binds (cytokines) JAK recruited to phosphorylatr the receptor which then recruits STAT STAT is phosphorylate - now active and localises to the nucleus to affect transcription
Describe the G protein coupled receptor
7-pass transmembrane protein Act via an intracellular second messenger system eg. cAMP, inositol, IP3, diacylglycerol (DAG) The G proteins are heterotrimeric- alpha, beta and gamma subunits Activation of a receptor causes a confirmation change in the alpha subunit allowing GDP exchange for GTP releasing the alpha unit and the beta-gamma complex forms a functional unit These act as second messengers
eg. After hormone is bound and alpha subunit released, DAG activates PLC➡ IP3 changes Ca levels➡ calmodulin➡ calmodulin-activated kinases And PKC Results in phosphorylated target proteins
Describe steroid hormone receptors
Ligands are small and lipophilic. Most steroid hormones travel in blood bound to protein carriers to help them circulate. Balance in blood between bound and unbound steroid hormone and it is only the unbound steroid hormone that can enter cells. Few with cell surface receptors Most receptors are in the cytoplasm and as a complex binds to a gene target Type 1 receptors- work as homodimers eg. Glucocortoid, mineralcorticoid, progesterone, oestrogen and androgen Active transport to nucleus AMD bind to sequences of DNA called hormone response elements (HREs) Type 2 receptors- heterodimerise with RXR eg. VDR, RAR, TR Retained in nucleus When not ligand bound in complexes with co-repressor proteins, ligand binding recruits co-activator proteins in which additional proteins like RNA polymerase are recruited to translate DNA into mRNA
Described the structure of nuclear receptors
Conserved AF1 at the N terminal, DNA binding in the middle and AF2 near the C terminal AF1+2 work synergistically for transcriptional activation
Describe HRE
Hormone response elements. Specific to hormones and are binding sites. Cytoplasmic or nuclear
Monomeric- A/T rich region 5’ to half-site
Dimeric- Pal HRE- palindrome or inverted DR HRE- direct repeat IP HRE- inverted palindrome Recognised by P-box on zinc fingers
THe DNA binding area is known as the P-box. It contains zinc finger recogising sequances for hormone response elements.
Describe the orgnaisation of the hypothalamus
A collection of brain nuclei or centres which have impoortnat control and integrative functions Important for homeostasis and primitive functions Controls autonomic functions via brainstem autonomic centres Controls endocrine function via the pituitary gland,
Responds tp enviromental factors, neural signals and hormones
List some hypothalamic hormones
Thyroid releasing hormone- TRH Gonadotrophin Releasing hormone- GnRH Growth hormone releasing hormone- GHRH Somatostatin Corticotropin releasing hormone- CRH Dopamine Small peptides Release is pulsatile inducting rapid effects on the release of cognate anterior pituitary hormone
Describe the pituitary gland
Anterior pituitary hormones regulated by secreted hypothalamic factors Posterior pituitary hormones synthesised in hypothalamus and transported via neural projections Structurally continuous with the hypothalamus by the pituitary stalk
List the anterior pituitary cell types and the hormone they secrete hormones
Thyrotroph- thyroid stimulating hormone (TSH) Corticotroph- adrenocorticotrophic hormone (ACTH) Gonadotroph- luteinizing hormone and follicle stimulating hormone (LH/FSH) Somatotroph- growth hormone (GH) Lactotroph- prolactin (PRL) Single chain hormones- PRL, GH Two chain glycoproteims: common alpha + unique beta- TSH, LH, FSH
ANTERIOR PRODUCE: TSH, LH, FSH, ACTH, GH, Prolactin
List the posterior pituitary hormones
ADH (Vasopressin) Neurophysins Oxytocin
What is POMC?
A large precursor polypeptide that is ther source of several important biologically active substances including: ACTH Gamma-MSH Beta-LPH (corticotroph cell)➡ gamma-LPH+ beta-endorphin (brain)
What are the different types of secretion?
Constitutive Regulated Pulsatile Diurinal
Describe thyroid stimulating hormone
TSH is made in thyrotrophs in the anterior pituitary is response to pulsatile TRH release in the hypothalamus
Pituitary failure can result in secondary hypothyroidism
Pituitary tumour can result in secondary hyperthyroidism
Describe gonadotrophins
LH and FSH Made by gonadotrophs (most make both, some only make one) in the anterior pituitary on response to GnRH Regulate testosterone biosynthesis and spermatogenesis in the testes Regulate menstruation and fertility in the ovary Both act through cell membrane receptors coupled to Gs proteins➡ cAMP➡ PKA
Describe adrenocorticotropic hormone
ACTH Synthesised by corticotrophs in the anterior pituitary Stimulates GPCR coupled to cAMP stimulates enzymes that convert cholesterol to cortisol or sex steroid hormones (eg StAR)
Describe prolactin
Made in lactotrophs- production increases during pregnancy due to increase in oestrogen Inhibits its own release (negative feedback by dopamine having a negatvie infleuence on it) Stimulates mammary gland development via DNA synthesis, epithelial cell proliferation, synthesis of lactose, casein, lactalbumin, free fatty acids Maintains lactation via synergy with glucocorticoids, inhibited by oestrogen and progesterone
What is a prolactinoma?
Most common pituitary tumour Interfere with HPG axis resulting in infertility, amenorrhoea, galactorrhoea Treatment with dopamine agonists
Describe growth hormone
Released by somatotrophs Pulsatile secretion Stimulated by low glucose, exercise and sleep
Protein hormone carried by proteins
Release inhibited by somatostatin Deficiency or resistance: GH receptor mutations- laron syndrome dwarfism- treated with IGF1 GH deficiency- treated with recombinant hGH
Describe ADH
Nonapeptide suyntheised by the posterior pituitary
Packaged with the carrier protein neurophysin in secondary granules in the magnocellular neurones of the periventricular and supraptic nuclei. Released upon the stimulaiton of the nerves
Acts in collecting ducts in the kidneys- aquaporins. ADH stimulates the production of aquaporins which let water be reabsorbed
Diabetes insipidus- posterior pituitary damage may reduce ADH and urine cannot be concentrated. Causes excess urine production
Describe oxytocin
Synthesised in the posterior pituitary
Stimulates contraction of smooth muscle of the breast and uterus
Can be given to induce labour
Neuro-endocrine reflexes
