BIOL1XX8_2024_L4_HomeostasisFeedbackLoops.pdf

Homeostasis Signalling Feedback Loops Human Biology 2024 Philip Poronnik Payne Scott Distinguished Professor School of Medical Sciences Faculty of Medicine and Health Major Concepts How do we maintain stability in the body? Feedback loops – positive and negative How do cells/tissues/organs communica...

Homeostasis Signalling Feedback Loops Human Biology 2024 Philip Poronnik Payne Scott Distinguished Professor School of Medical Sciences Faculty of Medicine and Health Major Concepts How do we maintain stability in the body? Feedback loops – positive and negative How do cells/tissues/organs communicate with themselves and the outside world? STIMULUS - SENSOR – CONTROL - EFFECTOR Homeostasis Homeostasis Maintenance of internal consistency – tendency to counteract change NEGATIVE feedback upper limit set point lower limit Feedback Loops Negative – counteract changes from “set-points” (eg body temp, blood glucose) moving back to equilibrium – analogy - toilet paper stocks Positive – amplify initial stimuli to move system further away from its starting point – analogy - toilet paper during lockdown Childbirth Bloodclotting In order to maintain homeostasis, we need systems that can control our entire body The nervous system sends very fast electric messages to our body A slower acting chemical based messaging system that helps maintain homeostasis – the endocrine system Our Endocrine system In this system, a variety of organs throughout our body release chemicals into our bloodstream. When these chemical messengers arrive at cells in our body – they tell those cells how to behave and act A hormone is a chemical/organic molecule messenger made by endocrine cells https://youtu.be/Og9XKqZNJ3E What is the endocrine system? Endocrine – an internal secretion that pertains to a gland that secretes directly into the bloodstream Endocrine gland – a ductless gland that produces an internal secretion discharged into the blood or lymph and circulated to all parts of the body Exocrine – external secretion via ducts to epithelial surface ??If it is circulated to all parts of the body – how can there be specific actions??? https://www.endocrine.org/patient-engagement GENERAL FUNCTIONS OF HORMONES Reproduction, growth and development Sex Steroids, thyroid hormones, prolactin, growth hormone Maintenance of internal environment Aldosterone, parathyroid hormone, vitamin D Energy production, utilization and storage Insulin, glucagon, thyroid hormones, cortisol, growth hormone Signalling Points to ponder… How does insulin work?? How does it talk to the cell?? Has to bind to interact with something on the membrane That has to then tell the cell that insulin is present and to do something about it… Insulin is a signalling molecule - a LIGAND It binds to a RECEPTOR High affinity interaction with ligand High specificity for ligand Specific distribution patterns within body Many different types Lock and key system Receptor and ligand How do you get specificity if hormone is everywhere?? Like a radio signal – have to have a receiver (receptor)… Therefore hormones TARGET organs/cells expressing the specific receptors Signalling = Cellular decision making… In response to an external stimulus Signal leads to cell response secrete, contract, move, divide, die, survive, catabolize, form tight junctions, release neighboring cell, kill neighboring cell, differentiate – or any subset of the above “Water soluble” hormones Peptide hormones can’t cross membrane Require transmembrane receptors Receptor then transduces signal Signal AMPLIFICATION Phosphorylation Cascades… Mediated by enzymes called KINASES – these transfer phosphate and activate target proteins Phosphate = PO4- Second messengers – the key intermediate… Molecules whose presence is a signal Act as amplifiers Synthesized or released from storage Act as intracellular ligands Made or released by effector proteins What do you need to be a 2nd messenger?? Low amounts in resting state Regulated synthesis Regulated destruction Act through other proteins * Cyclic AMP * Calcium Adenylyl cyclase turns ATP into cyclic AMP ATP – adenosine triphosphate… cellular energy!! What regulates [cAMP]?? Adenylyl Cyclase (AC) makes it from ATP… LOTS of ATP (~1 mM in cytoplasm) cAMP then activates KINASES What regulates AC?? GPCR signalling G proteins bind GTP (same as ATP but guanosine instead of adenosine G protein-coupled receptor activated G protein mobilised G protein activates effector (AC) cAMP produced and cascade is commenced!! Hormone Glucagon – enzymic conversion of glycogen to glucose in liver receptor Adenylate cyclase AC G cAMP ATP cAMP sensitive activators cAMP cAMP cAMP cAMP Amplification!!!!! What about calcium??? [Ca2+] is SO low that a dramatic increase acts as a “call to action” Calcium has profound effects on protein activity, Interactions, conformation Ca2+ 1x10-7M 1x10-3M Ca2+ ATP 10,000 fold gradient!!! Calcium waves upon fertilization Slower mobilisation of calcium Where is calcium in the cell ?? Calcium as a second messenger Activation of membrane receptors Calcium FLOODS into the cells VERY quickly!! In turn changes cellular actions at all levels… Think NEUROTRANSMITTERS…!! Calcium plays a major role in triggering synaptic vesicle exocytosis and the release of neurotransmitters. When an action potential propagates down the axon of a nerve and arrives at the axon nerve terminal it activates voltage-gated calcium channels causing an increase in intracellular calcium at the active zone. Cardiac myocyte Calcium signals between cells in exocrine pancreas Steroid receptors Mechanism of hormones that can readily enter cells Oestradiol as example - oestradiol secreted from ovaries acts various target organs (i.e. uterus, vagina, mammary glands skin, brain) Cause growth (production of proteins), also responsible for endometrial growth and involved in menstruation Receptor DNA complex Feedback Loops THE MASTER GLAND THE PITUITARY Extensive vascularisation Posterior Pituitary 2 main hormones Oxytocin ADH - antidiuretic hormone (vasopressin) supraoptic nucleus - neuroendocrine cells Oxytocin oxy- quick ; tokos - childbirth Uterine contractions Breast milk ejection Mammary alveolus Myoepithelial cells ADH – antidiuretic hormone (vasopressin) ADH released in response to - rise in osmolarity of blood - fall in blood pressure - fall in blood volume Primary action to prevent water loss through kidneys (diuresis = increase in urine) Aquaporins!!