Endo (NER)

• Hormones are substances secreted into blood by specialised cells, in small conc in blood, bind to specific receptors at target cells to affect cellular reactions
• endocrine system maintains homeostasis via feedback mechanisms - usually negative
• Negative feedback: stimulus → gland releases hormone A → acts on target tissue to cause effect + release of hormone B →hormone B decreases stimulation of gland
• Main endocrine glands – hypothalamus, pituitary, thyroid, parathyroid, adrenal, pancreas, ovary & testes
• Hormone superfamilies – amino acid derivatives, peptide, steroid
• Catecholamines & peptide hormones are fast acting, Steroid hormones are slower acting
• Peptide hormones – water soluble so stored in vesicles & released by exocytosis; often produced as preprohormones (inactive, signal peptide cleavage produces inactive prohormone); synthesis via transcription, translation & modification
• Preprohormones consist of prohormone, signal peptide & inactive fragment
• Amino acid derived hormones – synthesised from amino acids, incl. thyroid hormones & catecholamines
• Steroid hormones – produced on demand from cholesterol in adrenals & gonads; lipophilic so easily diffuse across membranes so not stored long; rate of synthesis limited by cholesterol transport into mitochondria by STAR; incl glucocorticoids, androgens & Vitamin D
• Hormone action can be fast (when altering function of already produced protein) or slow (when altering gene expression so need transcription & translation) responses
• Examples of hormones & actions incl. – testosterone controls masculinity & sexual function, vitamin D controls calcium regulation, aldosterone controls blood pressure
• Hormone receptor requirements – bind specific hormone at high affinity, but reversibly. Only found in specific tissues, saturable & cause a biological response
• hormone receptors can be intracellular or cell surface/extracellular. Extracellular receptors incl. TK linked & GPCRs
• TK Linked receptor action – hormone binding --> conformational change in kinase --> phosphorylation of Tyr residue in protein. TK activity can be recruited or intrinsic.
• recruited tyrosine kinase activity - phosphorylation factor recruited e.g. GH receptors. intrinsic tyrosine kinase activity - dimerization exposes kinase domain for factor phosphorylation e.g. EGFR
• EGFR activity – EGF binds to extracellular domain --> receptor dimerization --> kinase domain exposure --> phosphorylation --> factor recruitment & phosphorylation via exchange of GDP for GTP
• Ras is a small GTPase activated by exchange of GDP for GTP
• Examples of TK linked receptors incl. EGFR, GHR, Insulin receptor
• JAK-STAT signalling – GH or prolactin binds to TKR --> conformational change --> JAK binds & phosphorylates receptor --> STAT recruitment --> STAT self-phosphorylates, dissociates & travels to nucleus to allow transcription
• GPCRs – 7 transmembrane domains; involve a second messenger e.g. cAMP, IP3, DAG; hormone binding --> a-subunit of GP exchanges GDP for GTP --> conformational change activates a-subunit --> a-subunit dissociates & activates second messenger