Introductory Physiology Lectures – S1A PDF

1 Introductory Physiology Lectures – S1A Foundations for understanding Systems & Integrated Physiology Overview and Scientific Process Think! Systems, tissues, cells (genes), body water How the body...

1 Introductory Physiology Lectures – S1A Foundations for understanding Systems & Integrated Physiology Overview and Scientific Process Think! Systems, tissues, cells (genes), body water How the body is organised Transport processes (across cell membranes) Basis for Understanding Bio-electric potentials (and ion distribution) System Function Nerve Physiology Just 1 of 11 systems Muscle plus the other 9 systems and integration The other 10 Dr Ruane-O’Hora, (Dr Markos, Dr Healy) systems 2 Lecture Learning Outcomes Action potentials in nerve cell axons Explain why APs propagate in one direction Role of neuroglia / myelin sheath Specialised sensory cells Describe mechanism of synaptic transmission Role of Synapses in Neuronal Circuits Local anaesthetics versus neurotoxins – mechanism of action 3 Action Potentials Sensory cell Synapse Sensory cell Axon Nerve terminals I Synapse Sensory cell Axon and Nerve terminals II (NT = neurotransmitter) 4 Two questions… Q1. What are action potentials ? A1. Small identical electrical changes in individual parts of a neuron… Q2. But what’s actually happening in an axon? 5 Diffusion times of ions to acheive 99% equilibrium Distance (µm) Time (s) Nerve 0.1 0.000 000 5 synapse Synaptic transmission can work by diffusion Typical 10 0.05 Cell Graded potentials can work by diffusion Longest 1,000,000 (1 metre) 500,000,000 (15 years) Nerve But how can nerve impulses work by diffusion? 6 Graded potentials +30 Na+ mV -70 mV -70 Voltage-gated Na+ and K+ channels in axon 7 Graded potentials +30 Na+ mV -70 mV -70 8 Graded potentials +30 mV -70 mV -70 Na+ Na+ 9 Graded potentials +30 mV -60 mV -70 Na+ Na+ Na+ Na + Na+ Na+ Na+ 10 Decision Point +30 mV -55 mV -70 Na+ Na+ Na+ Na+ Na+ Na+ Na + Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ 11 Action potentials Very rapid changes in membrane potential – why and how? +30 mV -70 Na+ Na+ Na+ Na+ Na+ Na + Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Voltage-gated Na+ and K+ channels in axon  Resting membrane potential (RMP) 12 Inside is negative relative to outside –70 mV Na+ K+  Graded potentials 13... increases membrane potential to -55 mV Na+ K+  At -55 mV Na+ channels open 14... increases membrane potential to +30 mV Na+ K+ Influx of Na+ is extremely rapid because... Na+ gradient is large and Electrical gradient is large  Na+ channels close at peak of AP 15 Maximum Potential +30mV Na+ K+  K+ channels open at +30 mV 16... decreases membrane potential to –90 mV Na+ K+ Efflux of K+ is extremely rapid because... K+ gradient is large and Electrical gradient is large  Na+ / K+ pump helps resets RMP 17 Membrane Potential –70 mV Na+ K+ Na+ / K+ Pump 18 Voltage-regulated Na+ channel has three states: closed – open – inactivated Ready (closed) triggered by summation of graded potentials Biological timer switch - remains open for 1 msec Biological timer switch – channel inactive for ~2 msec "refractory period" 19 Voltage-regulated Na+ channel has three states: closed – open – inactivated triggered by summation of Open graded potentials Biological timer switch - remains open for 1 msec Biological timer switch – channel inactive for ~2 msec "refractory period" 20 Voltage-regulated Na+ channel has three states: closed – open – inactivated triggered by summation of graded potentials Inactivated Biological timer switch - remains open for 1 msec A new action potential cannot start Biological timer switch – channel inactive for ~2 msec "refractory period" during the “refractory” period 21 Voltage-regulated Na+ channel has three states: closed – open – inactivated Ready (closed) triggered by summation of graded potentials Biological timer switch - remains open for 1 msec A new action potential cannot start Biological timer switch – channel inactive for ~2 msec "refractory period" during the “refractory” period 22 Lecture Learning Outcomes Action potentials in nerve cell axons Explain why APs propagate in one direction Role of neuroglia / myelin sheath Specialised sensory cells Describe mechanism of synaptic transmission Role of Synapses in Neuronal Circuits Local anaesthetics versus neurotoxins – mechanism of action 23 AP at site A Na+ Na+ Na+ Na+ Na+ Na+ --- --- --- --- K++ K++ K++ K K K A B C 24 AP at site A Na+ Na+ Na+ Na+ Na+ Na+ --- --- --- --- K++ K++ K++ K K K A B C 25 AP at site A Na+ Na+ Na+ Na+ --- --- --- --- K++ K++ K++ Na K+ K K Na+ A B C 26 AP at site A raises mem pot to threshold on either side (pre-hillock and site B) K+ Na+ Na+ K+ Na+ Na+ --- --- --- --- K++ K++ Na + K K Na+ A B C 27 AP at site A raises mem pot to threshold on either side (pre-hillock and site B) No Na+ channels before the axon hillock so nothing happens K+ Na+ Na+ K+ Na+ Na+ --- --- --- --- K++ K++ Na+ K K Na+ A B C 28 AP at site A raises mem pot to threshold on either side (pre-hillock and site B) No Na+ channels before the axon hillock so nothing happens Na+ channels in site B are activated and AP occurs at site B K+ Na+ Na+ K+ Na+ Na+ --- --- --- --- K++ K++ Na+ K K Na+ A B C 29 AP at site B K+ Na+ Na+ K+ Na+ Na+ --- --- --- --- K++ K++ Na+ K K Na+ A B C 30 AP at site B K+ Na+ K+ Na+ --- --- --- --- K+ K++ Na+ + K+ K Na Na+ Na+ A B C 31 AP at site B raises mem pot to threshold on either side (site A and site C) K+ K+ Na+ K+ K+ Na+ --- --- --- --- K++ Na+ + K Na Na+ Na+ A B C 32 AP at site B raises mem pot to threshold on either side (site A and site C) Na+ channels at site A are in refractory state so nothing happens K+ K+ Na+ K+ K+ Na+ --- --- --- --- K++ Na+ K Na+ Na+ Na + A B C 33 AP at site B raises mem pot to threshold on either side (site A and site C) Na+ channels at site A are in refractory state so nothing happens Na+ channels in site C are activated and AP occurs at site C K+ K+ Na+ K+ K+ Na+ --- --- --- --- K++ Na+ K Na+ Na+ Na + A B C 34 AP at site C K+ K+ Na+ K+ K+ Na+ --- --- --- --- K++ Na+ K Na+ Na+ Na + A B C 35 AP at site C K+ K+ K+ K+ --- --- --- --- Na+ K + + Na+ Na+ K Na+ Na+ Na+ A B C 36 AP at site C raises mem pot to threshold on either side (site B and site D) K+ K+ K+ K+ K+ K+ --- --- --- --- Na+ Na+ Na+ Na+ Na+ Na+ A B C 37 AP at site C raises mem pot to threshold on either side (site B and site D) Na+ Channels at site B are in refractory state so nothing happens K+ K+ K+ K+ K+ K+ --- --- --- --- Na+ Na+ Na+ Na+ Na + Na + A B C 38 AP at site C raises mem pot to threshold on either side (site B and site D) Na+ Channels at site B are in refractory state so nothing happens Na+ Channels at site A are too far away to be activated K+ K+ K+ K+ K+ K+ --- --- --- --- Na+ Na+ Na+ Na+ Na + Na + A B C 39 AP at site C raises mem pot to threshold on either side (site B and site D) Na+ Channels at site B are in refractory state so nothing happens Na+ Channels at site A are too far away to be activated Na+ Channels in site D are activated; AP occurs at site D K+ K+ K+ K+ K+ K+ --- --- --- --- Na+ Na+ Na+ Na+ Na + Na + A B C 40 Repeated APs when sufficient stimulus If stimulus on sensory cell remains sufficiently high....... graded potential at axon hillock remain high and APs will be repeatedly generated... -55 mV ++++ ++++ - - - - ++++ ++++ - - - - - - - - ++++ - - - - - - - - Site A Site B Site C Site D Site E - - - - - - - - ++++ - - - - - - - - ++++ ++++ - - - - ++++ ++++ 41 Repeated APs when sufficient stimulus If stimulus on sensory cell remains sufficiently high....... graded potential at axon hillock remain high and APs will be repeatedly generated... -55 mV - - - - ++++ ++++ - - - - ++++ ++++ - - - - - - - - ++++ - - - - Site A Site B Site C Site D Site E ++++ - - - - - - - - ++++ - - - - - - - - ++++ ++++ - - - - ++++ 42 Repeated APs when sufficient stimulus If stimulus on sensory cell remains sufficiently high....... graded potential at axon hillock remain high and APs will be repeatedly generated... -55 mV ++++ - - - - ++++ ++++ - - - - - - - - ++++ - - - - ++++ ++++ Site A Site B Site C Site D Site E - - - - ++++ - - - - ++++ ++++ ++++ - - - - ++++ ++++ - - - - 43 Repeated APs when sufficient stimulus If stimulus on sensory cell remains sufficiently high....... graded potential at axon hillock remain high and APs will be repeatedly generated... -55 mV ++++ ++++ - - - - ++++ ++++ - - - - - - - - ++++ - - - - - - - - Site A Site B Site C Site D Site E - - - - - - - - ++++ - - - - - - - - ++++ ++++ - - - - ++++ ++++ 44 Repeated APs when sufficient stimulus If stimulus on sensory cell remains sufficiently high....... graded potential at axon hillock remain high and APs will be repeatedly generated... And it’s really fast, as the sites are very close together, so distances are -55 mV short, and it all works by diffusion ! - - - - ++++ ++++ - - - - ++++ ++++ - - - - - - - - ++++ - - - - Site A Site B Site C Site D Site E ++++ - - - - - - - - ++++ - - - - - - - - ++++ ++++ - - - - ++++ 45 Repeated APs when sufficient stimulus If stimulus on sensory cell remains sufficiently high....... graded potential at axon hillock remain high and APs will be repeatedly generated... And it’s really fast, as the sites are very close together, so distances are -55 mV short, and it all works by diffusion ! ++++ - - - - ++++ ++++ - - - - - - - - ++++ - - - - ++++ ++++ Site A Site B Site C Site D Site E - - - - ++++ - - - - ++++ ++++ ++++ - - - - ++++ ++++ - - - - 46 Repeated APs when sufficient stimulus If stimulus on sensory cell remains sufficiently high....... graded potential at axon hillock remain high and APs will be repeatedly generated... And it’s really fast, as the sites are very close together, so distances are -55 mV short, and it all works by diffusion ! ++++ ++++ - - - - ++++ ++++ - - - - - - - - ++++ - - - - - - - - Site A Site B Site C Site D Site E - - - - - - - - ++++ - - - - - - - - ++++ ++++ - - - - ++++ ++++ 47 But no new APs generated when stimulus stops But when stimulus on sensory cell stops....... graded potential at axon hillock falls below -55 mV, and no new APs are generated -70 mV ++++ ++++ - - - - ++++ ++++ - - - - - - - - ++++ - - - - - - - - Site A Site B Site C Site D Site E - - - - - - - - ++++ - - - - - - - - ++++ ++++ - - - - ++++ ++++ 48 But no new APs generated when stimulus stops But when stimulus on sensory cell stops....... graded potential at axon hillock falls below -55 mV, and no new APs are generated -70 mV ++++ ++++ ++++ - - - - ++++ - - - - - - - - - - - - ++++ - - - - Site A Site B Site C Site D Site E - - - - - - - - - - - - ++++ - - - - ++++ ++++ ++++ - - - - ++++ 49 But no new APs generated when stimulus stops But when stimulus on sensory cell stops....... graded potential at axon hillock falls below -55 mV, and no new APs are generated -70 mV ++++ ++++ ++++ ++++ - - - - - - - - - - - - - - - - - - - - ++++ Site A Site B Site C Site D Site E - - - - - - - - - - - - - - - - ++++ ++++ ++++ ++++ ++++ - - - - 50 But no new APs generated when stimulus stops But when stimulus on sensory cell stops....... graded potential at axon hillock falls below -55 mV, and no new APs are generated -70 mV ++++ ++++ ++++ ++++ ++++ - - - - - - - - - - - - - - - - - - - - Site A Site B Site C Site D Site E - - - - - - - - - - - - - - - - - - - - ++++ ++++ ++++ ++++ ++++ 51 Lecture Learning Outcomes Action potentials in nerve cell axons Explain why APs propagate in one direction Local anaesthetics & role of neuroglia / myelin sheath More synapses and neuronal circuits Specialised sensory cells Describe mechanism of synaptic transmission Role of Synapses in Neuronal Circuits Local anaesthetics versus neurotoxins – mechanism of action 52 Local Anaesthetics? What would happen to nerve impulses if a drug that blocked voltage-gated Na+ channels was administered? +30 mV -55 -70 mV Na+ Na+ Na+ Na+ Na+ Na + Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Voltage-gated Na+ and K+ channels in axon 53 Local Anaesthetics? What would happen to nerve impulses if a drug that blocked voltage-gated Na+ channels was administered? +30 mV -55 -70 mV Na+ Na+ Na+ Na+ Na+ Na + Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Voltage-gated Na+ and K+ channels in axon 54 What is the role of myelin? nodes of Ranvier Myelin sheaths cause Na+ & K+ channels to aggregate in discrete regions along the axon Multiple Sclerosis (MS) is an auto- The gaps between myelin where Na+ & K+ channels immune disease where myelin is cluster are called nodes of Ranvier absent - inefficient AP transmission The spacing allows efficient propagation of APs 55 Nerve diameter affects conduction rates Nerve diameter directly proportional to conduction rate Conduction Velocity (m/sec) Fibre Diameter (µm) 56 Lecture Learning Outcomes Action potentials in nerve cell axons Explain why APs propagate in one direction Local anaesthetics & role of neuroglia / myelin sheath Specialised sensory cells Describe mechanism of synaptic transmission Role of Synapses in Neuronal Circuits Local anaesthetics versus neurotoxins – mechanism of action 57 Sensory Synapse Stimulus Promotes transmitter release Sensory Ca2+ receptor cell functional junction Transmitter between two cells Voltage-gated Ca2+ channel Afferent neuron Direction (sends signal to CNS) of AP To CNS 58 Sensory Synapses Stimulus Sensory synapses link the cells which detect changes in the body’s internal and external environment (examples on next few slides) to the nervous system Promotes transmitter release Sensory In most sensory synapses: receptor cell Ca2+ Stimulus triggers activation of voltage-gated Ca2+ channel Transmitter Ca causes release of transmitters 2+ Voltage-gated which diffuse across synapse… Ca2+ channel …and bind to receptors on afferent neuron which… Afferent neuron Direction (sends signal to CNS) … may, if stimulus is sufficient, of AP generate APs which are propagated along the neuron To CNS 59 Hearing Activation of voltage- gated Ca2+ channel causes release of neurotransmitters which diffuse across synapse and bind receptors on target cell Note – the extracellular fluid surrounding these cells is called “endolymph” which has a high [K+] 60 Vision Activation of voltage-gated Ca2+ channel causes release of neurotransmitters which diffuse across synapse and bind receptors on target cell Voltage-gated 61 Lecture Learning Outcomes Action potentials in nerve cell axons Explain why APs propagate in one direction Local anaesthetics & role of neuroglia / myelin sheath Specialised sensory cells Describe mechanism of synaptic transmission Role of Synapses in Neuronal Circuits Local anaesthetics versus neurotoxins – mechanism of action 62 Neuronal Synaptic Transmission Activation of voltage-gated Ca2+ channel causes release of neurotransmitters which diffuse across synapse and bind receptors on target cell 63 Neuronal Synaptic Transmission Activation of voltage-gated Ca2+ channel causes release of neurotransmitters which diffuse across synapse and bind receptors on target cell 1) Influx of Na+ ions from final Na+ channel in the axon – the action potential “arrives” Na+ 2) Activation of voltage-gated Ca2+ channel 3) release of neurotransmitters 4) which diffuse across synapse 5) and bind receptors on target cell and trigger response 64 Calcispetin blocks Ca2+ channels Activation of voltage-gated Ca2+ channel causes release of neurotransmitters which diffuse across synapse and bind receptors on target cell 1) Influx of Na+ ions from final Na+ channel in the axon – the action potential “arrives” Na+ 2) Activation of voltage-gated Ca2+ channel If Ca2+ channel blocked, no NT release, no synaptic transmission… …this can result in death 65 Synaptic Transmission - Signal Termination Activation of voltage-gated Ca2+ channel causes release of neurotransmitters which diffuse across synapse and bind receptors on target cell 1) Influx of Na+ ions from final Na+ channel in the axon – the action potential “arrives” Na+ 2) Activation of voltage-gated Ca2+ channel 3) release of neurotransmitters 4) which diffuse across synapse 5) and bind receptors on target cell and trigger response But the signal must also be terminated if the APs stop - how? Remove the NT from the synapse 6) Degrade it by membrane bound enzyme 7) Take it back up into pre-synaptic cell 8) Diffusion out of the synapse 66 Synaptic Transmission and Anti-depressants Failure to transmit information properly is thought to contribute to some cases of clinical depression. How can drugs be used to improve synaptic transmission? 1) Influx of Na+ ions from final Na+ channel in the axon – the action potential “arrives” Na+ 2) Activation of voltage-gated Ca2+ channel 3) release of neurotransmitters 4) which diffuse across synapse 5) and bind receptors on target cell and trigger response But the signal must also be terminated if the APs stop - how? Remove the NT from the synapse 6) Degrade it by membrane bound enzyme 7) Take it back up into pre-synaptic cell 8) Diffusion out of the synapse 67 Synaptic Transmission and Anti-depressants Failure to transmit information properly is thought to contribute to some cases of clinical depression. How can drugs be used to improve synaptic transmission? Na+ Target step 6 If a drug can block the enzyme which degrades the NT, the NT concentration will remain higher for longer so more nerve transmission will occur e.g. Nardil and Marplan 6) Degrade it by membrane bound enzyme 68 Synaptic Transmission and Anti-depressants Failure to transmit information properly is thought to contribute to some cases of clinical depression. How can drugs be used to improve synaptic transmission? Na+ Target step 7 If a drug can block the reuptake of NT, the NT concentration will remain higher for longer so more nerve transmission will occur e.g. Prozac 7) Take it back up into pre-synaptic cell 69 Nerve:Muscle Synpase (Neuro-Muscular Junction) APs activate voltage-gated Ca2+ channels which causes release of acetylcholine (NT) which diffuses across synapse, binds receptors on target cell and triggers muscle contraction 70 Nerve:Muscle Synpase (Neuro-Muscular Junction) APs activate voltage-gated Ca2+ channels which causes release of acetylcholine (NT) which diffuses across synapse, binds receptors on target cell and triggers muscle contraction Target of curare More Na+ in than K+ out - why? See later 71 Nerve:Muscle Synpase (Neuro-Muscular Junction) An Excitatory Synapse which triggers muscle contraction Curare - plant extract used in hunting Blocks ACh binding to receptor, therefore muscle cannot contract Paralyses muscle Animal dies from respiratory failure 72 Lecture Learning Outcomes Action potentials in nerve cell axons Explain why APs propagate in one direction Local anaesthetics & role of neuroglia / myelin sheath Specialised sensory cells Describe mechanism of synaptic transmission Role of Synapses in Neuronal Circuits Local anaesthetics versus neurotoxins – mechanism of action 73 Synaptic Transmission Some definitions… Synapses can be excitatory (+ve) or inhibitory (-ve) All examples (except one) so far trigger APs - they are called excitatory synapses (e.g. taste, neuromuscular junction) But some synapses can prevent APs, so-called Inhibitory synapses (e.g. visual, inter-neurons) …and an example A hot meal on your family’s best plate! 74 Motor neuron - no APs Muscle relaxed No grip “Why inhibitory interneurons are important” 75 Motor neuron - high freq APs Muscle contracts Strong grip “Why inhibitory interneurons are important” 76 Motor neuron - no APs Muscle relaxed No grip “Why inhibitory interneurons are important” 77 Afferent neuron connected to temperature receptor APs if you touch hot object Motor neuron - high freq APs Temperature Muscle contracts receptor Strong grip “Why inhibitory interneurons are important” 78 Brain Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to muscle in hand No AP - no grip 79 Brain Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to muscle in hand No AP - no grip 80 Brain: ooh, there’s a plate of chips! Brain Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to muscle in hand No AP - no grip 81 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to muscle in hand No AP - no grip 82 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to muscle in hand APs - hold object 83 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Input: Plate is hot Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to muscle in hand APs - hold object 84 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Input: Plate is hot Output (reflex): Drop plate Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to muscle in hand APs - hold object 85 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Input: Plate is hot Output (reflex): Drop plate Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Spatial Summation 1 Yes + 1 No = No AP Inhibitory inter-neuron Motor neuron to Inhibitory inter-neuron sends APs muscle in hand which cancel out effect of APs from No APs - drop object brain  grip is released, but… 86 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Input: Plate is hot Output (reflex): Drop plate Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to muscle in hand No APs - drop object 87 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Input: Plate is hot Output (reflex): Drop plate Brain: it’s deadly hot, but it’s a family heirloom – I’m dead if it breaks! Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to Sending more APs muscle in hand down motor neuron No APs - drop object isn’t the answer! 88 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Input: Plate is hot Output (reflex): Drop plate Brain: it’s deadly hot, but it’s a family heirloom – I’m dead if it breaks! Output (conscious): take the pain! Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to Brain makes decision and sends APs which block muscle in hand the reflex inhibitory inter-neuron: inhibition of an No APs - drop object inhibitor = activation; grip is maintained 89 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Input: Plate is hot Output (reflex): Drop plate Brain: it’s deadly hot, but it’s a family heirloom – I’m dead if it breaks! Output (conscious): take the pain! Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Spatial Summation 1 Yes + 1 No = No AP Inhibitory inter-neuron Motor neuron to Brain makes decision and sends APs which block muscle in hand the reflex inhibitory inter-neuron: inhibition of an No APs - drop object inhibitor = activation; grip is maintained 90 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Input: Plate is hot Output (reflex): Drop plate Brain: it’s deadly hot, but it’s a family heirloom – I’m dead if it breaks! Output (conscious): take the pain! Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Spatial Summation 1 Yes + 1 No = No AP Inhibitory inter-neuron Motor neuron to Brain makes decision and sends APs which block muscle in hand the reflex inhibitory inter-neuron: inhibition of an APs - object held inhibitor = activation; grip is maintained 91 Brain: ooh, there’s a plate of chips! Brain Output: Touch the plate Input: Plate is hot Output (reflex): Drop plate Brain: it’s deadly hot, but it’s a family heirloom – I’m dead if it breaks! Output (conscious): take the pain! Descending inhibitory Heat Receptor neuron in skin of hand Motor neuron Inhibitory inter-neuron Motor neuron to Relatively muscle in hand Fast Slow speaking APs - object held Fast 92 Synaptic Transmission Synapses can be fast (mSec) or slow (Sec) Synapses can be excitatory (+ve) or inhibitory (-ve) So, how do they work? 93 Revision: voltage-gated ion channels change RMP Voltage-gated K+ channel K+ Voltage-gated Depolarise Repolarise Na+ channel Na+ Hyperpolarise Na+ will enter cells if Na+ channels are open – depolarise K+ will leave cells if K+ channels are open – repolarise or hyperpolarise 94 Revision: voltage-gated ion channels change RMP Voltage-gated K+ channel K+ Voltage-gated Depolarise Repolarise Na+ channel Na+ Hyper- Hyperpolarise polarise Na+ will enter cells if Na+ channels are open – depolarise K+ will leave cells if K+ channels are open – repolarise or hyperpolarise 95 Fast excitatory response Opening this channel causes 10x more Na in than K out, therefore membrane depolarises voltage increases quickly 5 milliseconds Fast: occurs as soon as channel opens (108 ions/sec) Ionotropic response: mediated by an ion channel Depolarisation in post-synaptic cell is called an EPSP: Excitatory Post-Synaptic Potential EPSPs are likely to trigger APs 96 Fast inhibitory response Open K+ channel, K+ leaves cells and membrane hyperpolarises voltage decreases quickly 5 milliseconds Iberiotoxin (red scorpion) blocks ion K+ channels Ionotropic response: mediated by an ion channel Hyperpolarisation in post-synaptic cell is called an IPSP: Inhibitory Post-Synaptic Potential IPSPs are likely to prevent APs 97 Slow Response - indirect channel opening Slow: ligand binds, conformational changes, voltage changes diffusion of proteins, then channel opens slowly 5 seconds Inhibitory or excitatory? - depends on nature of channel Metabotropic response: mediated by a GPCR 98 Summation & Convergence Many presyanptic cells synapse with cell body of one postsynaptic nerve Brain 99 Summation - a decision making process e.g. Temporal (one place, same time) Brain Output: Touch the plate EPSP - excitatory post-synaptic potential IPSP - inhibitory post-synaptic potential 10 Summation - a decision making process 0 e.g. Temporal (one place, same time) Two weak signals arriving several msec apart will not trigger AP - no grip Two weak signals arriving simultan- eously summate & trigger AP - grip EPSP - excitatory post-synaptic potential IPSP - inhibitory post-synaptic potential 101 Summation - a decision making process e.g. Temporal (one place, same time) Two weak signals arriving several msec apart will not trigger AP - no grip Two weak signals arriving simultan- eously summate & trigger AP - grip EPSP - excitatory post-synaptic potential IPSP - inhibitory post-synaptic potential 102 Summation - a decision making process e.g. Spatial (different space, but same time) Brain Output (reflex): Take the pain! EPSP - excitatory post-synaptic potential Brain makes decision and sends APs which block IPSP - inhibitory post-synaptic potential the reflex inhibitory inter-neuron: inhibition of an inhibitor = activation; grip is maintained 103 Summation - a decision making process e.g. Spatial A+A One EPSP = no AP = no grip One IPSP = no AP = no grip Two EPSP = AP = grip EPSP + IPSP = no AP = no grip EPSP - excitatory post-synaptic potential Brain makes decision and sends APs which block IPSP - inhibitory post-synaptic potential the reflex inhibitory inter-neuron: inhibition of an inhibitor = activation; grip is maintained 104 Summation - a decision making process e.g. Spatial A+A One EPSP = no AP = no grip One IPSP = no AP = no grip Two EPSP = AP = grip EPSP + IPSP = no AP = no grip EPSP - excitatory post-synaptic potential Brain makes decision and sends APs which block IPSP - inhibitory post-synaptic potential the reflex inhibitory inter-neuron: inhibition of an inhibitor = activation; grip is maintained 105 Summation - a decision making process e.g. Spatial A+A One EPSP = no AP = no grip One IPSP = no AP = no grip Two EPSP = AP = grip EPSP + IPSP = no AP = no grip EPSP - excitatory post-synaptic potential Brain makes decision and sends APs which block IPSP - inhibitory post-synaptic potential the reflex inhibitory inter-neuron: inhibition of an inhibitor = activation; grip is maintained 10 6 Summation - a decision making process e.g. Spatial A+A One EPSP = no AP = no grip One IPSP = no AP = no grip Two EPSP = AP = grip EPSP + IPSP = no AP = no grip EPSP - excitatory post-synaptic potential Brain makes decision and sends APs which block IPSP - inhibitory post-synaptic potential the reflex inhibitory inter-neuron: inhibition of an inhibitor = activation; grip is maintained 107 Lecture Learning Outcomes Action potentials in nerve cell axons Explain why APs propagate in one direction Local anaesthetics & role of neuroglia / myelin sheath Specialised sensory cells Describe mechanism of synaptic transmission Role of Synapses in Neuronal Circuits Local anaesthetics versus neurotoxins – mechanism of action 108 Pain-free Novocaine / Lidocaine block voltage gated Na+ channels preventing nerve impulses (AP) - LOCAL anaesthetics life Novocaine Lidocaine 109 Pain-ful Tetrodotoxin (TTX) blocks voltage gated Na+ channels preventing nerve impulses - NEUROTOXIN death Stage 1 (20 mins - 3hrs) - slight numbness of the lips and tongu - sensations of lightness or floating, headache, nausea, diarrhea, and/or vomiting Stage 2 (4 to 6 hours) - increasing paralysis - inability to sit, respiratory distress and hypotension - paralysis increases and convulsions, mental impairment, and cardiac arrhythmia may occur. - the victim, although completely paralyzed, may be conscious and in some cases completely lucid until shortly before death Between 1974 - 1983 646 reported cases of fugu (pufferfish) poisoning in Japan, with 179 fatalities. 1 mg administered systemically can be fatal to humans S1A summary Overview Module Objective: To lay the foundations for understanding Systemic and Integrated Physiology Lectures 1 - 3: Systems, Tissues, Cells, Genes and Body Water How the body is organised Bodily functions are defined by 11 overlapping systems There are only four tissue types in the body - Nerve - Muscle - Epithelial - Connective Tissues are made from cells - the function of cells is dictated by the genes they express, that is, the proteins that they synthesize… … all nucleated cells contain all genes: Physiology Nobel Prize 2012 A 70 kg human comprises 42 L of water - 28 L inside cells (ICF) Ionic compositions vary, but - 14 L surround cells (ECF) osmolarity is the same Lectures 4 - 5: Transport processes (across cell membranes) Basis for Understanding System Function Movement of ions and molecules is by Brownian motion If lipid bilayer is permeable, or made permeable by a carrier protein, ions or molecules will cross the lipid bilayer passively down their chemical gradient - Fick’s law: dn/dt = PC Ions and molecules can move against their chemical gradient by active transport using pumps or transporters - energy provided by ATP or chemical gradients of other ions or molecules An understanding of transport processes explains water homeostasis, and led to the biggest medical breakthrough of the 20th Century - Oral Rehydration Therapy Transport processes essential to explain all aspects of physiology Lectures 6 - 7: Nerve impulse generation, propagation & inhibition Introduction to one of three body systems Nervous system relays information from one part of body to another Activation of nerve cells causes graded potentials of nerve cell body If threshold is reached, APs are generated and propagated along the length of the axon resulting in NT release in axon terminal APs continue to propagate along the axon for as long as the activation threshold is reached An understanding of nerve physiology will help explain how muscles are controlled (integration of different systems)...... and also explains how neurotoxins, local anaesthetics and anti- depressants work, and how they might be improved! What’s next…? See details on Canvas PL1001 / PL1400 All the other systems in Physiology….