CSB346 Lecture 6 Review Notes

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University of Toronto St. George
Cell and Systems Biology
John Peever

CSB346 Lecture 6 Summary – Central Chemoreception Function of chemoreceptors - Breathing depends on input from chemoreceptors - Chemoreceptors provide information about blood/tissue levels of O2 and CO2 - Carotid bodies = O2 and CO2 chemoreceptors - CNS = CO2 chemoreceptors o CO2/pH levels are related to acid-base balance in the blood and brain o CO2/pH levels reflect adequacy of lung ventilation to tissue metabolism  Lung ventilation is designed to meet metabolic demands (e.g., producing more CO2 is a powerful drive to breathe more rapidly to get rid of the CO2) 1. ↓ CO2 by extracorporeal gas exchange unit = ↓ ventilation o Level of ventilation correlates with CO2 production o Venous blood  extracorporeal gas exchange unit (remove CO2)  vena cava  Gas exchange entirely by lamb  Breathing is normal  Gas exchange is partly by lamb and partly by extracorporeal circuit  Breathing is decreased  Gas exchange is completely by extracorporeal circuit  Breathing is stopped 2. ↓ PCO2 by hyperventilation = apnea o Depends on state of consciousness (e.g., anaesthesia)  In wakefulness, hypocapnia causes breathing to stop briefly  In sleep, hypocapnia causes apnea o Hyperventilation does not change PO2 o Central chemoreceptors are crucial in monitoring CO2 levels and regulating ventilation 3. ↑ PCO2 by inhalation of CO2 = ↑ ventilation (↑ respiratory frequency and ↑ tidal volume) o Ventilatory response to increases in CO2 (e.g., slope)  Cannot be altered by conscious thought  Potentiated/increased by hypoxia  Decreased during sleep o Ventilation doubles for every 2 mmHg rise in PCO2 Central versus peripheral chemoreceptors - Shows that there are two distinct thresholds for ventilatory response to increases in CO2 o Central + peripheral (CB intact)  When CB intact, rapid ventilatory response to increases in CO2 o Central + no peripheral (CB denervated)  When no CB/peripheral, delayed ventilatory responseto increases in CO2 - 2 distinct thresholds for breathing o Central chemoreceptors take longer to detect changes in CO2 o Peripheral chemoreceptors detect changes in CO2 quickly - 2 types of responses o Not proof that there are two sets of chemoreceptors o Peripheral chemoreceptors respond first o Central chemoreceptors respond second Central CO2-sensitive zones - 3 regions on the ventral surface of brainstem responded to focal acidification (↓pH) o L = Loeschcke o S = Schlafke o M = Mitchell Location of central chemoreceptors - Fastigal nucleus (FN) - Retrotrapezoid nucleus (RTN) - Nucleus of solitary tract (NTS) - Locus coeruleus (LC) - Pre-BotC - Medullary raphé (MR) How do cells sense pH changes? - CO2 is rapidly hydrated to carbonic acid, which dissociates into a proton and bicarbonate ion o CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3- o ↑ CO = ↓ pH and vice versa - Both intracellular and extracellular pH is a stimulus for central chemoreception o Extracellular pH is sensed by respiratory-modulated neurons o Intracellular pH is sensed by neurons in the LC and MR - More than one pH-sensing function may operate simultaneously - It is possible that different mechanisms at different chemoreceptor locations 1. Neuronal ion channels o pH-sensitive proteins detect pH changes, which affect neuronal excitability  Membrane ion transport proteins (e.g., Na+/H+ exchange protein)  Gap junctions  TASK channels  K+ channels  In current clamp, Kir channels detect PCO2 changes (e.g., hypercapnia or hypocapnia) o Looking at how the current across the cell membrane changes in response to intracellular pH changes  Current is an index of ions moving across the cell membrane  affects the excitability of the cell  ↓ current = hyperpolarization = ↑ excitability o ↓ pH = ↓ current = ↓ K+ is moving out the cell  Membrane potential is more positive  Cell excitability is increased o The cell is not dead because this is reversible o This does not tell you anything about breathing  In situ hybridization, Kir channels are in brainstem cardio-respiratory neurons  Therefore, Kir channels contribute to the CO2/pH sensitivity in these neurons 2. Intrinsic cell membrane property o Most neurons in the midline medullary raphé do not respond to changes in pH o Only some are able to detect and respond to pH changes  ↑ CO2 = depolarization or hyperpolarization  Also neurons in the LC, NTS, and caudal raphé 3. Synaptic transmission o Synaptic transmission can be affected by a receptor, or the release, synthesis, or uptake of a neurotransmitter (e.g., acetylcholine, serotonin, glutamate) o Experiment 1  VRG contains all three musca
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