BMS100_PHL1-23_W23_Homeostasis.pdf

Physiology Concepts IV Homeostasis and Intercellular Signaling BMS 100 Week 6 Today’s Overview Concepts in feedback Steady-state vs. equilibrium Classical negative feedback Positive feedback and feed-forward loops Homeostasis Definitions and components Homeostasis vs. negative feedback Cellula...

Physiology Concepts IV Homeostasis and Intercellular Signaling BMS 100 Week 6 Today’s Overview Concepts in feedback Steady-state vs. equilibrium Classical negative feedback Positive feedback and feed-forward loops Homeostasis Definitions and components Homeostasis vs. negative feedback Cellular vs. organism-level homeostasis Fundamentals of intercellular signaling Paracrine and autocrine Endocrine and neurological signaling Basic considerations • 1865 – Claude Bernard stated that the stability of the internal environment is crucial for life • This was later refined in 1900 by Charles Richet: § “The living system is stable…it must be in order not to be destroyed, dissolved or disintegrated by colossal forces, often adverse, which surround it. • By an apparent contradiction, it maintains its stability only if it is excitable and capable of modifying itself according to external stimuli and adjusting its response to the stimulation. • In a sense, it is stable because it is modifiable – the slight instability is the necessary condition for the true stability of the organism.” Billman, G. Front. Physiol. 2020; 11: 200 Basic considerations • Walter Cannon – coined “homeostasis” in 1963 • Current definition: § self-regulating process by which biological systems maintain stability while adjusting to changing external conditions • Most models of homeostasis are more sophisticated than this simple statement § Stability = a particular physiologic parameter that is monitored and maintained within a relatively narrow range at all times § Examples of parameters – blood glucose levels, body temperature, blood pressure, ECF osmolarity Billman, G. Front. Physiol. 2020; 11: 200 Constancy vs. homeostasis • Equilibrium: § When a process proceeds in the forwards and backwards direction at the same rate – no net change occurs • i.e. a chemical reaction § No energy is expended or regulation occurs – this is not homeostasis • Dynamic steady state: § When a process or system exerts energy to maintain a particular state § This state is not at equilibrium • Example – the Na+/K+ pump moves sodium out of the cell, preventing swelling (maintaining a constant volume) § However, this steady state is not monitored with clear feedback loops and sensors (that we know of)* • therefore not (quite) homeostasis A model of homeostasis • Homeostasis as defined by physiologists has all of these components • Before understanding how homeostasis works, we need to understand the components Modell et. al. Adv Physiol Educ 39: 259–266, 2015; doi:10.1152/advan.00107.2015 So… what is homeostasis? First – definition of terms: • Regulated variable – a parameter that is measured in the body with sensors and is kept within a set of limits § Limit = between a low and a high range • i.e. extracellular pH – between 7.35 and 7.45 § This is the “thing” that homeostasis is devoted to regulating • Sensor – a process that can measure the regulated variable and deliver a signal about that variable § Sometimes signals only happen when the regulated variable falls outside of the “normal” range § Usually signaling is constant, reflecting the overall state of the regulated variable § This can be a cell, or a biochemical reaction, or a channel, or a tissue – good example is a baroreceptor Modell et. al. Adv Physiol Educ 39: 259–266, 2015; doi:10.1152/advan.00107.2015 So… what is homeostasis? Definition of terms cont... • Control centre – has a controller and an error detector § Error detector à “calculates” the difference between the set-point value of the regulated variable and the actual value of the regulated variable and sends an error signal to the controller § Controller à sends output signals to effectors that can change the regulated variable depending on data (error signal) from the error detector • Set point – the range of values of the regulated variable that the system tries to maintain § Very difficult to “find where the set-point exists” in a biologic system § i.e. – how does the error detector in the brainstem “know” what the normal pH is supposed to be? • No one has really figured this out Modell et. al. Adv Physiol Educ 39: 259–266, 2015; doi:10.1152/advan.00107.2015 So… what is homeostasis? Definition of terms cont... • Effector – what the controller manipulates to “get the job done” § Effectors respond to information from the controller and change the value of the regulated variable • They will change the regulated variable in such a way that it comes closer to the setpoint • Nonregulated variable – effectors usually change values of the non-regulated variable in order to bring the regulated variable closer to the set point § For example – if your pH drops, then your respiratory rate increases in order to “get rid of” excess carbon dioxide § Regulated variable à pH § Non-regulated variable à respiratory rate Modell et. al. Adv Physiol Educ 39: 259–266, 2015; doi:10.1152/advan.00107.2015 Are homeostasis and negative feedback the same? • Although homeostasis can (and usually does) use negative feedback loops, not all negative feedback loops are homeostatic • The simplest negative feedback loop: ABCase ABC AB + C A+B+C Are homeostasis and negative feedback the same? • In this simple negative feedback loop the process resulted in the production of a product § ABCase produces A, B, and C • That product inhibited the process § “B” inhibits ABCase, reaction slows down • Negative feedback = output of a system is fed back in a manner that tends to reduce the fluctuations in the output § Tends the products tend to oscillate between low and high points, depending on how “fast” the product inhibits the process ABCase ABC AB + C A+B+C Are homeostasis and negative feedback the same? • Note that there is no: § Control centre § Set point § Error signal § Regulated variable • Therefore, this is not what physiologists consider homeostasis ABCase ABC AB + C A+B+C Baroreceptor review Major baroreceptors: • carotid arteries • arch of the aorta Pressure drops à message sent to the brainstem via nerves à 1. Activation of the sympathetic nervous system à release of epinephrine, norepinephrine 2. Epi and NE à Elevation in HR and constriction of arterioles and increased stroke volume Anatomy & Physiology, 2e. p. 849, fig 20.26 https://openstax.org/books/anatomy-and-physiology-2e Aortic arch Blood pressure regulation as an example of homeostasis Use the information from the previous slide to identify: • The sensor The error detector The controller The effector The input and output signals • The non-regulated variables • • • • “Where” do you think the set-point lives? • Muscle spindle = a proprioceptor that senses muscle stretch Reflexes – the stretch reflex review • As the muscle is stretched: § activates the muscle to contract against the stretch by stimulating the motor neuron in the ventral horn § inhibits the antagonist muscle • Stretch caused by hitting the tendon with a reflex hammer Tortora and Derrickson, Principles of Anatomy and Physiology, 13th ed. p. 517, fig. 13.15 The Stretch Reflex • Is the stretch reflex a negative feedback system? • Is it a homeostatic system? § If not, what components of a homeostatic system are missing? Frequent homeostasis misconceptions Homeostatic mechanisms only “turn on” when the regulated variable is outside the setpoint • Untrue à § most sensors usually constantly deliver information to the control centre § The controller responds “more intensely” with a larger error signal… but it’s almost always sending input to the effectors at some basal rate “Mixing up” non-regulated and regulated variables • Example – sodium level stays in a relatively narrow range in our body’s ECF – it must be a regulated variable? § Nope – although potassium is regulated, sodium is not… § So why does sodium stay in such a narrow range? • See if you can find it in the next slide… Regulated variables in the ECF Regulated variable Normal range Sensor Control Centre Effector Effector Response Arterial oxygen 80 – 100 mm Hg Chemosensors (carotid, aortic) Brain stem Respiratory muscles Altered respiratory rate Arterial CO2 35 – 45 mm Hg Chemosensors (carotid, aortic) Brain stem Respiratory muscles Altered respiratory rate [K+] 3.5 – 5.0 mmol Chemosensors (adrenal) Adrenal Kidneys, many other tissues Altered K+ reabsorption, secretion [Ca+2] 2.2 – 2.6 mmol/L Chemosensors (parathyroid) Parathyroid Kidneys, bone, intestine Altered calcium reabsorption, secretion pH 7.35 – 7.45 Chemosensors (brainstem, carotid, aortic) Brainstem Respiratory muscles Altered respiratory rate Blood glucose 4 – 8 mmol Chemosensors (pancreas) Pancreas Liver, skeletal muscle, fat Altered glucose metabolism Osmolarity 280 – 296 mOsm Chemosensors (hypothalamus) Hypothalamus Kidneys Sodium and water reabsorption A second-tosecond tracing of BP regulation • Individuals had their BP monitored moving from lying to standing (see labels) • Note that the systolic and diastolic pressures fluctuate continually – they’re never constant… § Therefore the controller, the error detector, the sensor, and the effectors are all active at every moment § Oscillations are a typical feature of homeostatic systems V.K. van Wijnen et. al. J Int Med 2017 https://doi.org/10.1111/joim.12636 Other important homeostatic systems Regulated variable Normal Range Sensor Control Centre Effector Effector Response Core body temperature 35.5 – 37.5 Celsius Thermosensor (hypothalamus, skin) Hypothalamus Blood vessels, Shivering, sweat glands, sweating, skeletal muscle distribution of blood Mean arterial 85 – 100 pressure mm Hg Baroreceptor (aortic, carotid) Brain stem Heart and blood vessels Change in heart rate, stroke volume, vascular tone Blood volume 5 L Heart, kidneys Medulla Heart, kidneys Change in heart rate, stroke volume, vascular tone, and fluid/salt retention **Note how all of the homeostatic systems discussed involve regulated parameters of some component of the extracellular fluid Typical features of homeostatic systems • Systems tend to overlap, rather than be isolated § For example: blood pressure regulation is obviously interrelated with fluid volume regulation and osmoregulation in the ECF § pH regulation and arterial CO2 regulation are also interrelated • Effectors can be “turned up” or “turned down” to achieve homeostasis, or different effectors can be called upon to control the regulated variable § BP regulation – effectors are “turned up” or “turned down” § Glucose regulation – separate metabolic pathways are activated in hyperglycemia vs. hypogycemia Typical features of homeostatic systems • Oscillations in the regulated variable are typical § Regulated variables fluctuate constantly § Disease states can cause larger fluctuations that are unstable § Disease states sometimes can be due to altered set points • Best example here – hypertension is partially a “set point error” disease • Redundancy is common § The more vital the parameter, the greater number of systems that regulate it Other regulatory mechanisms • Positive feedback: § Output of a system is fed back in a manner that tends to increase that system’s output § Tends to result in an exponential “increase” in the output, until a limiting event is reached • Example: see parturition (childbirth) positive feedback loop in the next slide § Limiting event – baby is expelled through the birth canal, ending the feedback loop Alberts et. al. Molecular Biology of the Cell Basics of the parturition reflex: • Baby’s head presses on & thins the cervix à • Cervical thinning & stretch is detected by mechanoceptors and transmitted to the brain à • The hypothalamus releases oxytocin in response à • Oxytocin causes uterine contraction, forcing the baby against the cervix à Tortora and Derrickson, Principles of Anatomy and Physiology, 13th ed., fig. 1.5 Feed-forward loops • Feed-forward loop = a system where changes in a regulated variable are anticipated, and the controller “pro-actively” activates an effector § Example – visualizing performance prior to an athletic event • Heart rate, stroke volume, BP, respiratory rate increase § Example – muscle proprioceptors detect an increase in activity • Signals to the respiratory centre to increase ventilatory rate before any changes in blood gases occur Review – Complexity of regulation of ventilation System/region or Sensor Details Cerebral Cortex Voluntary control of respiratory rate Hypothalamus Regulates respiratory rate based on emotional state, pain, body temperature set-points à tells the brainstem to change ventilation Proprioceptors When your muscles and joints move, sends a signal to your brainstem à your ventilation changes in anticipation of increased MSK oxygen and carbon dioxide exchange needs Chemoreceptors Increase ventilation when arterial oxygen drops and carbon • Peripheral dioxide increases • Central à Very strong influence on ventilation Feed-forward? Feed-back? Physiology Concepts IV Homeostasis and Intercellular Signaling Part II Dr. Hurnik BMS 100 Week 6 Homeostasis – cells vs. organisms • The model of homeostasis that you’ve used is best at describing control of a regulated parameter at the “organism level” • Cells do have regulated variables, sensors for them, effectors, and set-points § It is difficult to study cellular homeostasis, though • the molecular and biochemical networks that keep the internal environment constant are very complex and (obviously) small • Often difficult to measure or locate controllers, error detectors, set points § Our body’s strategy – keep the internal environment constant so that our cells aren’t in a “hostile environment” that’s difficult to regulate Intercellular signaling How do cells signal to each other? • Contact § Membrane receptors contact the ECM or another cell (ligand) à an intracellular signal in one (or both) cells • Paracrine § Cell “A” produces a soluble messenger which diffuses to a cell “B” à binding to a membrane receptor on cell “B” à an intracellular signal in cell “B” Intercellular signaling How do cells signal to each other? • Endocrine § Cells in endocrine organs release a chemical messenger into the bloodstream à circulation of the messenger (hormone) à an intracellular response in any cell that has a receptor for that hormone • Nervous § A neuron “A” sends an electrical signal along an axon to a synapse with cell “B” à release of a neurotransmitter à binding of neurotransmitter to a receptor on cell “B” à an intracellular response § Cell “B” could be another neuron, a muscle cell (smooth, skeletal, cardiac), or an endocrine cell Four major types of signaling Alberts et. al. Molecular Biology of the Cell, 2014. fig. 15-2 Short-distance signaling • Contact § Important for embryologic development, immune signaling, and for limiting/organizing growth § Example – epithelial cells contact the basement membrane via hemidesmosomes • Integrins are part of the hemidesmosome complex – when they bind the ECM, intracellular signals are generated • These signals help determine polarity (which way is “up”) Short-distance signaling • Paracrine § Very common signaling mechanism whereby cells signal locally to each other, via a soluble mediator § Wide range of uses • Immunological/defence, signals of local damage • Regulation of growth/cell division/tissue repair • Local regulation of blood flow § Everyday (every second) example: • Metabolically active tissue releases metabolites (H+, CO2, K+) that cause local vascular endothelial cells to relax à • Vasodilation and improved blood flow Long-distance signaling Endocrine • Mechanism: § Organ secretes a messenger into the blood stream à § Messenger is widely distributed throughout the body à § Cells with receptors for the messenger respond • Two major structural (and strategic) branches: § Hypothalamic-pituitary system • The hypothalamus controls the endocrine secretions of the pituitary gland • Pituitary secretions act on another target gland or organ Long-distance signaling Endocrine • Two major structural (and strategic) branches cont… § “Other” endocrine glands • These glands are not under hypothalamic or pituitary control • Usually they directly sense a stimulus (they are the sensor and the control centre) and secrete a hormone in response to that stimulus • Examples: § Pancreas and GI tract § Parathyroid glands § Adipose tissue Endocrine system • Which of these glands are under hypothalamic control? • Can you identify any missing endocrine organs? Hypothalamic-Pituitary System – a closer look • The hypothalamus sits just under the thalamus and is connected to the pituitary gland via a vascular stalk • The pituitary gland sits within the sella turcica § Where is that? Which cranial bones? • General model: § Hypothalamic signal à stimulates pituitary cells à pituitary cells release a hormone à hormone acts on another gland (usually endocrine) à “target” gland secretes larger quantities of a hormone à general systemic response Hypothalamic-pituitary system – anterior pituitary Hypothalamic-pituitary system – anterior pituitary • The hypothalamus secretes releasing or inhibiting hormones into 1st set of capillaries • These travel down to the anterior pituitary and modulate hormone secretion from those cells • Anterior pituitary hormones control a number of other endocrine glands § Thyroid, adrenal gland, gonads, liver Hypothalamic-pituitary system – posterior pituitary • Hypothalamic neurons project to the posterior aspect of the pituitary • The axons of these neurons release hormones into the capillaries in the posterior pituitary • Major hormones secreted: § ADH and oxytocin § Both of these act directly on target tissues, not on other glands Fluid homeostasis and the pituitary – ADH • ADH (anti-diuretic hormone) controls water balance in the body § One of the two hormones secreted by the posterior pituitary § Other is oxytocin (hormone that controls the positive feedback loop of childbirth) • ADH secretion is controlled by the osmolarity of the blood – when the blood is more concentrated (i.e. less water), then ADH is secreted § When ADH is secreted, then more water is “recovered” by the kidneys and kept in the bloodstream § When ADH decreases, more water is lost in the urine • Blood osmolarity is detected by osmoreceptors in the hypothalamus Fluid homeostasis and the pituitary – ADH • Plug ADH signaling into this model, same as for baroreceptors An example of anterior pituitary signaling – thyroid hormone • Thyroid hormone release is regulated by the hypothalamus in response to cardiovascular parameters and “metabolic” parameters (such as body temperature) • Also released in a particular rhythm to help facilitate growth of the organism An example of anterior pituitary signaling – thyroid hormone An example of anterior pituitary signaling – thyroid hormone • Note the negative feedback loops: § Thyroid hormone negatively feeds back on the anterior pituitary and the hypothalamus § TSH negatively feeds back on the hypothalamus § Typical of hypothalamic-pituitary signaling