Nerve, Muscle and Synapse Physiology Study Notes PDF

Nerve, Muscle and Synapse Physiology Lecture 1 recording 1: An Introduction to the Nervous System An Introduction to Neuroscience: ▪ The nervous system is made of the: o Central nervous system → brain and spinal cord o Peripheral nervous system...

Nerve, Muscle and Synapse Physiology Lecture 1 recording 1: An Introduction to the Nervous System An Introduction to Neuroscience: ▪ The nervous system is made of the: o Central nervous system → brain and spinal cord o Peripheral nervous system → nerves that serve the neck and arms, trunk, legs, skeletal muscles and internal organs The Stretch Reflex: ▪ The stretch reflex is the simplest stimulus- response paradigm that the human nervous system can generate ▪ Stretch reflex → muscle contraction in response to stretching within muscle ▪ Patellar-tendon stretch reflex: tap the patellar tendon which attaches to the quadriceps muscle → quadriceps muscle stretches, making the quadriceps muscle longer → activation of nerve impulses in special receptors (stretch receptors) located in the quadriceps muscle → nerve impulses are sent back to the spinal cord along the sensory neuron, and activate another nerve cell which feeds back out onto the quadriceps muscle, activating this muscle and causing it to contract → a jerk or swing of the foot outwards The Withdrawal Reflex: ▪ (This is another reflex we will look at) Components of the Nervous System: ▪ Central nervous system (CNS): o Brain and spinal cord  o Composed of the cerebral cortex, the cerebellum, the brain stem and the spinal cord o The spinal cord is anatomically similar along its entire extent ▪ Peripheral nervous system (PNS): o Comprised of peripheral nerves, receptors in our muscle in the stretch reflex that signal muscle stretch and axons of nerve cells which connect the spinal cord to the muscles Lecture 1 recording 2: Cells of the Nervous System and Reflexes Cells of the Nervous System: ▪ A neuron is a nerve cell (note a nerve cell is different from a nerve….will look at later) ▪ 2 types of cells in the nervous system: neurons and glia o Neurons make up about 10% of the total number of cells in the CNS but occupy 50% of the volume (bigger than glia) ▪ 3 different types of neurons: o Afferent neurons → take information from the periphery to the CNS o Efferent neurons → take information from the CNS back out to the periphery o Interneurons → carry information between neurons ▪ Afferent neurons and efferent neurons: only activate/excite o Afferent neurons make synaptic contact onto either efferent neurons directly or they may make excitatory contact onto interneurons o Efferent neurons make contact onto muscle (receive input from either afferent neurons directly, or from interneurons)  o Parts of the afferent and efferent neurons are always found in the PNS ▪ Interneurons can either excite or inhibit other neurons o Located entirely within the CNS (not found in the PNS) o Interneurons receive input from either afferent neurons or other interneurons o Make contact onto either efferent neurons or onto other interneurons The Stretch Reflex: ▪ Hammer tap of the patellar tendon results in muscle stretch → activates the afferent neuron → afferent neuron travels to the spinal cord and synapses with an efferent neuron → efferent neuron travels back to the periphery and results in the quadriceps muscle contraction More Cells of the Nervous System: ▪ Glia: o The glue of the nervous system o 90% of the cells in the nervous system and occupy ~ 50% of the volume of the nervous system o Include: oligodendrocytes, Schwann cells, astrocytes, microglia Oligodendrocytes and Schwann cells → make myelin. Oligodendrocytes make myelin in the CNS and Schwann cells in the PNS. Spinal Cord: Interface for Reflexes: ▪ Spinal cord has two main components: gray matter and white matter. Gray matter is a horn or butterfly shape, and white matter surrounds the horn or butterfly shape.  ▪ When afferent neurons and efferent neurons innervate a muscle, they are separated from each other around the muscle o The neurons travel towards the CNS within a mixed peripheral nerve or a spinal nerve o A mixed peripheral nerve contains both afferent fibers and efferent fibers o Afferent neurons → carry information from the periphery to the spinal cord via the dorsal roots o Efferent neurons → carry information from the spinal cord to the periphery via the ventral roots o Interneurons → carry information between neurons and located entirely within the CNS Spinal Cord: Interface for Reflexes: ▪ Afferent information comes in through the dorsal part of the spinal cord and efferent information leaves the ventral part of the spinal cord ▪ Reflex loop: o Circular in nature. o Activation of a receptor will activate an afferent fiber which enters through the dorsal root of the spinal cord. This will activate an efferent fiber which leaves through the ventral root of the cord. The efferent fiber will activate a muscle. ▪ Myelin o Made by oligodendrocytes in the CNS o Coats the axons of neurons and allows them to transmit the nerve impulses much more quickly o Myelinated axons of neurons are found in the white matter of the spinal cord o White matter appears white because it contains myelinated axons of neurons (myelin gives a white appearance)  ▪ Gray matter contains largely cell bodies of interneurons and unmyelinated processes. Due to the lack of myelin, gray matter does not look white. The Stretch Reflex: ▪ Tendon tap of the patellar tendon results in stretching of the quadriceps muscle → stretching activates stretch receptors which are connected to afferent neurons → information is sent from the muscle back to the spinal cord through the afferent neuron indicating that the muscle has been stretched → afferent neuron travels with efferent neurons in the mixed peripheral nerve until it gets just outside the spinal cord → afferent neuron enters through the dorsal root of the spinal cord and contacts an efferent neuron of the ventral part of the cord → efferent neuron exits through the ventral root of the spinal cord → efferent neuron travels via the mixed peripheral nerve to the quadriceps muscle and results in its contraction ▪ Interneurons: o Involved in the stretch reflex o Can be either excitatory or inhibitory o Always located entirely within the CNS o Interneuron in the stretch reflex is inhibitory. The afferent nerve fiber also synapses with an inhibitory interneuron. When activated, the inhibitory interneuron inhibits efferent neurons which innervate the hamstrings muscle. This inhibits contraction of the hamstrings muscle so that it does not interfere with the reflex response. Lecture 1 recording 3: Neuron Structure Neuron Structure and Polarity: ▪ A neuron: o Is a nerve cell  o Contains: Dendrites → receive information from periphery or from other cells Cell body → also called a soma; contains nucleus Axon hillock → very initial segment of the axon; integrates/processes information coming into the dendrites and generates a nerve impulse if there is enough input Axon → propagates nerve impulses from initial segment to axon terminals Axon terminals/synaptic terminals → contains neurotransmitter in synaptic vesicles ▪ Information in the nervous system flows in one direction only: it flows from dendrites and cell bodies down the axon towards axon terminals ▪ Synapse – junction between 2 neurons ▪ Presynaptic neuron – the neuron before the synapse ▪ Postsynaptic neuron – the neuron after the synapse Types of Neurons ▪ Neurons have different morphologies but they have the same ‘parts’ (dendrites, cell body, axon, axon terminals) ▪ Afferent neuron in stretch reflex is a pseudo-unipolar cell The Stretch Reflex ▪ Afferent neuron of stretch reflex: o Sensory neuron which takes information from muscle stretch to the CNS o Pseudo-unipolar cell o Cell body located in dorsal root ganglion o Peripheral axon – extends from the cell body to  the muscle o Central axon – from cell body into CNS and makes contact with other neurons Neuron Structure ▪ Myelinated axon – allows nerve impulses to move more quickly Neuron Structure ▪ (This is a summary slide of the structure of a neuron. We will continue to look at the different parts of the neuron and talk about them in more detail) The Stretch Reflex ▪ Afferent neuron: o Pseudo-unipolar cell o Peripheral axon of the afferent neuron extends to the muscle and receives stretch input from the quadriceps muscle o Central axon of the afferent neuron arises from the cell body and extends to the CNS o Makes two synapses, or two contacts, onto other neurons (the efferent neuron to quadriceps muscle and an inhibitory interneuron) Afferent neuron makes direct monosynaptic contact onto the efferent neuron which innervates the quadriceps muscle ❖ The excitatory efferent neuron which travels to the quadriceps muscle is activated, resulting in contraction of the quadriceps Afferent neuron synapses with an inhibitory interneuron ❖ The afferent neuron is excitatory and activates an inhibitory interneuron. The inhibitory interneuron makes contact  onto an efferent neuron which innervates the antagonistic muscle, which is the hamstring. ❖ Contact onto the inhibitory interneuron inhibits the efferent neuron travelling to the hamstrings muscle and inhibits the hamstrings muscle from contracting. ▪ When the quadriceps muscle is stretched by tapping the patellar tendon, the quadriceps muscle is activated to contract, while contraction of the hamstrings muscle is inhibited ▪ Interneurons and the two efferent neurons to the quadriceps and hamstrings muscles are multipolar cells: o Dendrites emanate from the cell body o The multipolar neurons have an axon whose axon terminals terminate in the muscle, affecting activity of the muscle Lecture 2 recording 4: The Resting Membrane Potential Membrane Structure: ▪ Neuron plasma membrane: o Phospholipid bilayer o Contains protein pumps and channels: Which set resting membrane potential of the cell (the neuron) Which allow and control movement of ions into and out of the cell Pumps – active transport; use an energy source to pump ions across the membrane Ion channels – do not use an energy source and are not active transport; allow ions to flow through down an electrochemical gradient  ❖ Passive channels – these are leak channels; always open and selective for a given ion ❖ Gated channels – require a stimulus to open the channel and allow ions to flow through ✓ Ligand-gated and voltage-gated channels Resting Membrane Potential (E ) m ▪ Resting membrane potential – a measure of the electrical potential difference between the intracellular environment and the extracellular environment o Charge separation between the inside and outside of the cell o At steady state, this charge separation is the resting membrane potential ▪ Resting membrane potential is ~ -70 mV (not the same for every cell!) o Most important ions involved in setting the resting membrane potential: sodium (Na ) and+ potassium (K ) + Chloride and organic anions play a minor role o Pumps/channels involved in setting resting membrane potential: Na /K pump, Na leak + + + channels, K leak channels + Chloride pump plays minor role Resting Membrane Potential (E ) m ▪ Na /K pump – active transporter involved in setting + + resting membrane potential Net Negative Charge is Set by the Na /K pump + + ▪ Na /K pump + + o Electrogenic :  Moves charge across the membrane 3 positively charged Na ions are pumped + out of the cell for every 2 positively charged K ions brought into the cell, moving a net of + 1 positively charged ion out of the cell for every cycle of the Na /K pump, resulting in + + a net negative charge inside the cell o Uses energy from ATP hydrolysis/breakdown (ATP → ADP + P ) i Na /K Pump Creates Gradients + + ▪ Within a cell there are: o Chemical gradients for Na and K + + o Electrical gradients (inside cell more negative than outside) ▪ Na /K pump + + o Creates the Na and K chemical gradients + + o Na outside cell > Na inside cell (Na wants to + + + diffuse into cell and Na pumped out by Na /K + + + pump) o K inside cell > K outside cell (K wants to + + + diffuse out of cell and 2 K pumped in by Na /K+ + + pump) ▪ Electrical gradient o Due to electrogenic nature of Na /K pump, + + inside of cell more negative than outside Lecture 2 recording 5: How is the Resting Membrane Potential Set? Resting Membrane Potential (E ): m ▪ Na /K pump sets up an unequal distribution of Na and + + + K ions across the cell membrane. + ▪ Na and K ions will try to achieve a state of + + equilibrium through the leak channels E is Set by Leak Channels: m  ▪ Leak channels: o Always open o Allow the passive flow of ions into/out of neuron o Selective for an ion o Ions move through based on electrical and chemical gradients E is Set by Leak Channels: m ▪ K concentration inside cell > K concentration outside + + cell (concentration gradient set by Na /K pump) + + ▪ Chemical force pushes K out of the cell through K + + leak channels ▪ Electrical force pushes K into the cell through K leak + + channels ▪ Chemical and electrical forces act on K at the same + time in opposite directions ▪ Equilibrium potential → the electrical potential at which K is completely at equilibrium + o Equilibrium potential for K = -90 mV + ▪ Remember: resting membrane potential is -70 mV o What will K be doing at the resting potential? + o K will move out of the cell, taking with it + positive charge, to try to move the resting membrane potential towards its equilibrium potential of -90 mV E is Set by Leak Channels: m ▪ Na concentration outside cell > Na concentration + + inside cell (concentration gradient set by Na /K pump) + + ▪ Chemical force pushes Na into the cell through Na + + leak channels ▪ Electrical force pushes Na into the cell through Na + + leak channels ▪ Chemical and electrical forces act on Na at the same +  time ▪ Equilibrium potential → the electrical potential at which Na is completely at equilibrium + o Equilibrium potential for Na = +55 mV + ▪ Remember: resting membrane potential is -70 mV o What will Na be doing at the resting potential? + o Na will move into the cell, taking with it + positive charge, to try to move the resting membrane potential towards its equilibrium potential of +55 mV E is Set by Leak Channels: m ▪ In an actual nerve cell, both Na and K are present + + ▪ How is the resting membrane potential of -70mV achieved? o The more permeable the membrane is to a given ion, the closer the resting membrane potential of that cell will be to that given ion’s equilibrium potential E is Set by Leak Channels: m ▪ The more permeant the ion, the greater its ability to force E towards its own equilibrium potential m o How is a membrane more permeable to an ion? By having more channels for that ion: ❖ There are more leak channels for K than + there are for Na in the membrane and the + membrane is therefore more permeable to K + ✓ The resting membrane potential (E ) is m closer to the equilibrium potential for K than for Na as there are more K + + + leak channels in the membrane compared to Na leak channels + ▪ Why do different cells have different resting membrane potentials? Cells have different ratios of K leak+  channels to Na leak channels + Lecture 2 recording 6: Review of the Resting Membrane Potential Review of Resting Membrane Potential (E ):m ▪ Activity of the Na /K pump creates an intracellular + + environment that is more negatively charged with respect to the extracellular environment ▪ Leak channels allow diffusion of ions down their electrical and chemical concentration gradients in an attempt to reach their own equilibrium potentials ▪K:+ o The electrical force pushes K into the cell + while the chemical force pushes K out of the cell + o K will move to try to achieve a membrane + potential closer to its equilibrium potential of -90mV o If the resting membrane potential of cell is not at -90 mV, K will leave the cell to try to bring + the resting membrane potential closer to -90 mV. ▪ Na : + o The electrical force and the chemical force push Na into the cell. + o Na will move to try to achieve a membrane + potential closer to its equilibrium potential of +55mV o At a resting membrane potential of -70 mV, Na + will move into the cell, trying to bring the cell closer to +55 mV Review of Resting Membrane Potential (E ):m ▪ At resting membrane potential passive ionic fluxes are balanced so that there is charge separation and E m remains constant  ▪ Value of resting membrane potential (-70 mV) is closest to equilibrium potential of ion with greatest membrane permeability: this ion is always K + Events at the Neuron Cell Membrane ▪ Resting membrane potential is -70mV due to Na /K + + pump and leak channels ▪ At a constant or resting membrane potential we do have the movement of ions, Na and K , across the cell + + membrane. K is being pumped in by the Na /K pump + + + and is leaving through the K leak channels. Na is + + being pumped out by the Na /K pump and coming + + back into the cell through the Na leak channels. + Lecture 3 recording 7: How is the Action Potential Generated? The Stretch Reflex: This section discusses how stretch of the quadriceps muscle results in generation of an action potential in the afferent neuron Action Potentials: ▪ The resting membrane potential is a steady-state condition determined by the relative permeability of the membrane to K and Na + + o When the patellar tendon is tapped, all the neurons in the stretch reflex (afferents, efferents and interneurons) are at resting membrane potential ▪ Specific stimuli disrupts the steady state-by causing ion selective channels in the membrane to open o In the stretch reflex, the physical stimuli is a stretching of the quadriceps muscle ▪ 2 main types of ion channels (other than the leak channels) in a neuron: o Voltage-gated ion channels  ❖ Opened at a specific membrane voltage o Ligand-gated ion channels ❖ Involved in neurotransmitter release and synaptic transmission ▪ An electrical signal, known as an action potential, is generated due to the activity of voltage-gated Na and + voltage-gated K channels + ▪ Action potential → large change of membrane potential from the resting membrane potential of ~ -70 mV and to ~ +30mV, approaching the equilibrium potential of Na (E = +55mV) + Na o Membrane potential does not quiet reach the Na equilibrium potential + o Membrane potential then falls back to the resting membrane potential of -70mV over a period of a few milliseconds (~2 to 3 milliseconds) ▪ Resting Membrane Potential (E ):m o Neurons are surrounded by a phospholipid bilayer o Within bilayer are the pumps and ion channels (passive and gated channels) ▪ How Are Afferents Activated?: o Afferent neuron embedded in the quadriceps muscle has a sensory receptor ❖ Senses muscle stretch o Muscle stretch (stretch reflex) or other sensory stimuli results in increased opening of specialized Na receptors, entry of Na into afferent fiber and + + depolarization of afferent neuron ❖ Muscle stretch = enlargement of sensory receptor and movement of Na ions through + pores in the sensory receptor  ❖ Slight depolarization of the membrane potential occurs due to the inward movement of positively charged Na + o There is a value of membrane potential in the cell which is called ‘threshold’; this value is the threshold for the opening of the voltage-gated Na + channels and the threshold for firing of an action potential ❖ Threshold is typically 10 to 15 mV more depolarized than resting membrane potential (we will use -50mV as threshold) ❖ If Na entry is sufficient to depolarize the + neuron to its threshold (~-50 mV) the result is the opening of voltage-gated Na channels + and an action potential ✓ When voltage-gated Na channels open, + permeability of the cell to Na increases + greatly (ie. LOTS of Na moves + through the voltage-gated Na channels + very quickly) ▪ Voltage-gated Ion Channels: o Note: Leak channels are open at resting membrane potential but voltage-gated Na + channels and voltage-gated K channels are + closed at rest o At rest, the outside of the cell is positively charged with respect to the inside (ie. the inside is negatively charged at rest) o Tap of patellar tendon → stretches quadriceps muscle → Na enters cell following stretch of the + sensory receptor → slight depolarization of the cell due to Na moving into cell (membrane + potential becomes more positive) → if threshold is reached (-50mV) voltage-gated Na channels +  open → at threshold, the activation gate is removed allowing Na to flow into cell → influx + of Na into cell brings membrane potential closer + to Na equilibrium potential → internal + compartment of cell changes from negatively charged to positively charged (+30mV) → around +30mV the inactivation gate closes Na + channel and Na cannot enter cell → activation + gate of voltage-gated K channel is removed and + K leaves cell removing positive charge → efflux + of K moves cell closer to the K equilibrium + + potential and the cell repolarizes o Open conformation of the voltage-gated Na + channels is only maintained for a few ms Lecture 3 recording 8: Phases of the Action Potential The Action Potential (2 slides): Understand the phases of the action potential and the events that occur during each phase (ie. which channels are involved, which ions are involved, what is the permeability to the ions or are the ion channels open or closed; see powerpoint file “Summary of Nerve-muscle Action Potential) ▪ The membrane potential of the cell is the result of the relative permeability of that cell to Na and K. + + o The resting membrane potential is entirely determined by the leak channels; at rest the membrane is more permeable to K than Na + + o During the action potential, voltage-gated Na + channels and voltage-gated K channels open and + close during the different phases ▪ Voltage-gated Na channels: + o Can be closed (or in “resting state”), open or  inactivated o In the inactivated state the Na channel is closed + and cannot be opened, even with stronger stimuli. In order to open the Na channel, it must return to + the ‘closed’ state again. ▪ Refractory period – absolute refractory period and relative refractory period o Absolute refractory period – time during which an excitable membrane cannot generate an action potential in response to any stimulus; due to inactivation of voltage-gated Na channels + o Relative refractory period - time during when an excitable membrane will generate an action potential but only to a stimulus of greater strength than the usual threshold strength Membrane Conductance: ▪ Conductance (g) – rate of ion travel through a channel ▪ Depolarization phase – Na conductance increases due + to opening of voltage-gated Na channels; conductance + decreases as voltage-gated Na channels inactivate + ▪ Repolarization phase – K conductance increases due to + the opening of the voltage-gated K channels; + conductance decreases as voltage-gated K channels + close Lecture 3 recording 9: Action Potentials: Transmission The Stretch Reflex: ▪ The movement of an action potential along a neuron is related to the relative permeabilities of Na and K + + Action Potentials: Transmission (3 slides): ▪ At rest inside the cell/neuron - negatively charged; outside the cell - positively charged. ▪ Step 1: Axon at resting membrane potential: o -70 mV  o Voltage-gated Na channels are closed + ▪ Step 2: Activation results in opening of voltage-gated Na channels: + o Activation of the stretch receptor results in a small amount of Na entering the axon; this will + bring this segment of the axon to threshold, resulting in the opening of the voltage-gated Na+ channels and the generation of an action potential, where the inside of the axon reaches ~+30 mV ▪ Step 3: Local depolarization of membrane causes adjacent voltage-gated Na channels to activate + o The opening of the voltage-gated Na channels + causes a local depolarization in a segment of the axon ▪ Step 4: New action potential is generate in adjacent membrane o The action potential is transmitted from segment to segment along the axon by local depolarization of the neighboring membrane ▪ Step 5: Action potential only travels in one direction due to refractory period Action Potentials: An Animation: ▪ During an action potential the inside of the cell membrane becomes positive with respect to the outside ▪ An action potential generates local currents which depolarize the membrane immediately adjacent to the action potential ▪ When depolarization caused by the local currents reaches threshold, a new action potential is produced adjacent to the original one ▪ Action potential propagation occurs in one direction  only due to refractory period Electrotonic Conduction: ▪ Electrotonic conduction → spread of current inside axon ▪ Summary: o Patellar tendon tap activates the stretch receptor located within the muscle o Na enters the cell through stretch receptors, +. bringing it to threshold and generating an action potential o AP initiated at one point in membrane o Current spreads electrotonically to adjacent membrane o Adjacent membrane depolarizes to threshold o New AP generated in adjacent membrane ▪ Electrotonic conduction proceeds in one direction only due to refractory period o Following an action potential the voltage-gated Na channels which opened for the action + potential will inactivate and must recover from this inactivation before they can open again Lecture 4 recording 10: Electrotonic Conduction and Myelination Electrotonic Conduction: (Review of electrotonic conduction) Electrotonic Conduction: ▪ The process of electrotonic conduction involves many steps, but an action potential would have to be regenerated at every point on the membrane for an impulse to travel from point A to point B along a neuron ▪ How can the speed of action potential propagation (electrotonic conduction) be increased?  o Myelination Cells of the Nervous System: ▪ Glia include oligodendrocytes and Schwann cells ▪ Myelin: o Made by oligodendrocytes in the central nervous system and Schwann cell in the peripheral nervous system Myelination: ▪ Lipid-protein mix ▪ An axon is wrapped with myelin, a process called ensheathing the axon ▪ Acts as an insulator and does not allow ions to move across axon where the myelin is present Lecture 4 recording 11: Nodes of Ranvier Nodes of Ranvier: ▪ Axon is the only part of a neuron that is myelinated (no myelin on cell body or dendrites; myelin stops just before axon terminals) ▪ Nodes of Ranvier: o Regions of a myelinated axon which are unmyelinated o Myelination is discontinuous along the axon o Contain the voltage-gated Na channels (ie. + voltage-gated Na channels are not found along + the axon in the myelinated regions) ❖ Voltage-gated Na channels are also found + clustered at the axon hillock, which is unmyelinated Nodes of Ranvier: ▪ In the peripheral nervous system: a single Schwann cell myelinates one segment of the axon ▪ In the central nervous system: a single oligodendrocyte myelinates several axons and several regions within a  given axon Lecture 4 recording 12: Saltatory Conduction and Speed of Propagation Saltatory Conduction: ▪ Propagation of action potentials along a myelinated axon such that the action potentials jump from one node of Ranvier in the myelin sheath to the next ▪ Is electrotonic conduction at the node of Ranvier ▪ Due to the presence of myelin, the neighbouring tissue is not depolarized at every point along an axon o The action potential is generated at the first node of Ranvier and then passes to the second node of Ranvier, where the process of depolarizing the neighboring tissue will then occur. The action potential can pass undiminished in size from node of Ranvier to node of Ranvier. o It is only at the nodes of Ranvier that depolarization of the neighbouring tissue and the opening of the voltage-gated sodium channels occurs Classification of Afferent Fiber Type: (You do not need to memorize the 4 types of fibers and diameters and speeds of conduction for the Nerve/muscle/synapse section. The key points for this slide are listed below:) ▪ 2 factors which determine the speed at which an axon propagates along axon potential from point A to point B: o Size of the axon: the thicker the axon is in diameter, the faster it can propagate an action potential o Myelination: myelinated axons propagate action potentials faster than unmyelinated axons  Speed of Propagation: ▪ By the time the absolute refractory period of any neuron, whether myelinated or unmyelinated, has been completed, the action potential has travelled far enough down the axon that there will not be depolarization of the neighbouring tissues ‘upstream’ ▪ The axon potential will always travel down the axon to the synaptic terminals or the axon terminals Lecture 4 recording 13: Synaptic Transmission Synaptic Transmission: ▪ The process whereby one neuron (nerve cell) communicates with other neurons or effectors, such as a muscle cell, at a synapse ▪ Stretch reflex: o Afferent neuron: ❖ Myelinated – action potential travels by saltatory and electrotonic conduction to spinal cord along afferent neuron o Afferent neuron activates the efferent neuron (to the quadriceps) and the inhibitory interneuron (inhibits efferent neuron to hamstrings) via chemical synaptic transmission Synaptic Transmission: (Shows figures for chemical and electrical synaptic transmission) Electrical Synapses: ▪ Electrical synapse o Physical connection between 2 cells which are very close together, allowing the passage of ions and small molecules o Connexin:  ❖ Protein channel connecting the 2 cells; each connexin made up of 6 connexin subunits ❖ Can be open or closed o Bidirectional o Fast communication between 2 cells Chemical Synapses: ▪ Involves a presynaptic cell and a post-synaptic cell with no physical connection ▪ Do not have bidirectional transmission – transmission from presynaptic cell to postsynaptic cell only Chemical Synapses: ▪ Definitive gap called the synaptic cleft or the synaptic gap between the presynaptic cell and the postsynaptic cell o As there is no physical connection between the presynaptic and postsynaptic cell, the presynaptic cell excites or inhibits the postsynaptic cell by release of a neurotransmitter ▪ Neurotransmitter is stored in the presynaptic terminal in synaptic vesicles ▪ Neurotransmitter is released from the vesicles and enters into the synaptic gap and binds to receptors on the postsynaptic cell ▪ Binding of neurotransmitter to receptors on the postsynaptic cell opens ion channels on the postsynaptic membrane, resulting in depolarization or hyperpolarization o Depolarization or hyperpolarization of the postsynaptic cell is based on which neurotransmitter is in the synaptic vesicles ❖ Neurotransmitters are inhibitory or excitatory Lecture 5 recording 14: More on Chemical Synapses  Chemical Synapses: ▪ Neurotransmitter is located inside vesicles in the presynaptic terminals ▪ Receptors for this neurotransmitter are found on the postsynaptic cell Resting Membrane Potential (E )m ▪ Neurotransmitter binds to ligand-gated ion channels at the chemical synapse o 2 types of chemical synaptic transmission: directly gated and indirectly gated synaptic transmission Chemical Synapses: Directly Gated ▪ Neurotransmitters: o Excitatory – glutamate; released by excitatory neurons o Inhibitory – glycine or GABA; released by inhibitory neurons ▪ Neuron is either excitatory or inhibitory; it cannot be both ▪ Directly-gated chemical synaptic transmission: o Neurotransmitter (NT) is released from vesicles in the presynaptic terminal o Neurotransmitter crosses the synaptic cleft/gap (~40 nanometers) and binds to receptors on the postsynaptic membrane o In directly gated chemical transmission the receptor is located on an ion channel ❖ Neurotransmitter binding to its receptor opens the ion channel ❖ Ions pass through the channel ❖ Glutamate is an excitatory neurotransmitter that opens a Na channel when it binds to a + receptor on the postsynaptic cell  ✓ Na will flow down its gradient into the + cell, making the cell more positively charged (the equilibrium potential for Na is +55 mV). This will result in a + depolarization of the membrane in the postsynaptic cell. ❖ GABA and glycine are inhibitory neurotransmitters that open a chloride channel or a potassium channel when they bind to their receptor on the postsynaptic cell. ✓ When a chloride channel or potassium channel opens this will make the inside of the cell more negative. This will result in a hyperpolarization of the membrane in the postsynaptic cell. i. If potassium channels have opened, potassium will leave the cell, taking with it positive charge ii. If chloride channels have opened, chloride will enter the cell, bringing with it negative charge o An action potential is not generated in the postsynaptic cell as threshold not reached: ❖ Excitatory NT → depolarizes postsynaptic membrane → EPSP ❖ Inhibitory NT → hyperpolarizes postsynaptic membrane → IPSP o Effects are fast in onset and short lasting (msec) receptor and the effecter are the same molecule ❖ Receptor is located directly on the ion channel Chemical Synapses: Indirectly Gated  ▪ Receptor and the effecter are not the same protein ▪ Neurotransmitter binds to receptor and activates 2nd messenger system in the postsynaptic cell (via G- proteins; GTP activates adenylyl cyclase which converts ATP into cAMP, the 2 messenger) nd ▪ cAMP activates protein kinases which phosphorylate a channel and cause it to open or close, causing changes in membrane permeability o Ions flow, resulting in depolarization or hyperpolarization ▪ Slow onset and long lasting Chemical Synapses versus Electrical Synapses ▪ Electrical synapses: o Inflexible o Coordinate the firing of many neurons at the same time o Are always excitatory ▪ Chemical synapses: o Provide flexibility o Only synapses which can generate inhibition (use inhibitory neurotransmitters GABA and glycine) o Specific neurotransmitters have specific effects on the postsynaptic membrane o Complexity can vary as synaptic transmission can be directly-gated or indirectly-gated o Time course can vary o Plasticity - refers to the process of indirectly- gated chemical synaptic transmission where long term changes in neurons are seen Lecture 5 recording 15: Synaptic Transmission: Excitatory versus Inhibitory Neuron Structure and Polarity:  ▪ Directly gated chemical synaptic transmission: direction of information flow is from presynaptic cell to postsynaptic cell Synaptic Transmission: ▪ An action potential is generated in the presynaptic neuron and travels down the neuron via electronic saltatory conduction (myelinated axon) ▪ When the action potential arrives at the presynaptic terminal, the presynaptic terminal depolarizes o The cell changes from negatively charged inside to positively charged inside ▪ Voltage-gated calcium channels in the presynaptic membrane open due to depolarization of the presynaptic membrane ▪ Calcium enters the cell through the voltage-gated calcium channels and causes vesicles containing neurotransmitter to move to and fuse with the presynaptic membrane ▪ Neurotransmitter is relealed into the synaptic gap or synaptic cleft by exocytosis from the vesicles once they have fused with the presynaptic membrane ▪ Neurotransmitter diffuses across the synaptic cleft to bind to a ligand-gated ion channel (neurotransmitter binds to receptors which are located directly on ion channels in the postsynaptic membrane) ▪ If it is an excitatory neurotransmitter (ie glutamate), the channels would be Na channels + o The binding of glutamate opens the Na + channels and Na flows through to depolarize the + postsynaptic cell o An EPSP, or excitatory post-synaptic potential, is generated ▪ If it is an inhibitory neurotransmitter (ie GABA,  glycine), the channels would be K or Cl channels + - o The binding of GABA or glycine opens the ion channels. Ions (K or Cl ) move to hyperpolarize + - the cell o If it is a K channel, K leaves the cell. If it is a + + Cl channel, Cl enters the cell. - - o An IPSP, or an inhibitory post-synaptic potential, is generated ▪ Neurotransmitter is released from its receptor and is either recycled or degraded Presynaptic Neuron Can Be Excitatory: ▪ Glutamate binds to receptor and opens ligand-gated Na + channels ▪ Na enters postsynaptic cell and results in small + depolarization known as excitatory postsynaptic potential (EPSP) ▪ EPSPs are subthreshold – it will move membrane potential towards threshold but one EPSP alone is not enough to generate and action potential Presynaptic Neuron Can Be Inhibitory: ▪ Inhibitory transmitters (GABA, glycine) bind to receptor and opens ligand-gated Cl channels (may also - be K channel) + ▪ Cl enters postsynaptic cell (K would leave the cell) and - + results in small hyperpolarization known as inhibitory postsynaptic potential (IPSP) and prevents generation of action potentials by moving cell away from threshold Lecture 5 recording 16: Synaptic Integration Neuron Structure and Polarity: ▪ How do EPSPs and IPSPs result in an action potential in the post-synaptic cell? This process is called synaptic integration  Synaptic Potentials Decay with Distance: ▪ Synaptic potentials are largest at the synapse where they originate ▪ Synaptic potentials (both EPSPs and IPSPs) decay as they travel away from the synapse along the neuronal membrane (decay with distance); they can only travel short distances as a result o Action potentials do not decay with distance ▪ Dendrites are not myelinated and have no voltage-gated Na channels + ▪ When an EPSP is generated in the post-synaptic membrane, depolarization of neighboring tissue can occur in both directions, both away from the cell body and towards the cell body. The main point of depolarization is at the synapse between the pre- synaptic terminal and the post-synaptic cell. Chemical Synapses: ▪ Synaptic potentials (EPSPs and IPSPs) ~ 0.2mV in magnitude and decay as they travel away from the synapse PSPs Summate: ▪ How do the synaptic potentials generate enough depolarization to bring the cell to threshold and generate an action potential as they are only 0.2mV in magnitude each and decay as they travel? o Answer: Summation of postsynaptic potentials or synaptic integration ▪ Many post-synaptic potentials are generated at any given time and they are additive ▪ 2 types of summation: temporal summation and spatial summation o Temporal summation – occurs when multiple postsynaptic potentials from a single presynaptic  neuron arrive at the cell body at a given point in time (single presynaptic neuron fires many times in succession) o Spatial summation – occurs when multiple postsynaptic potentials from different presynaptic neurons arrive at the cell body at the same time (different locations at the same time) ▪ A cell body may receive both excitatory and inhibitory presynaptic terminals o EPSPs and IPSPs may be generated on the cell body at the same time- they will add together and may cancel each other out (EPSPs are positive and IPSPs are negative) Lecture 5 recording 17: Synaptic Integration More On Synaptic Integration: ▪ Integration: process of summing together all the inputs into a pattern of action potential output in the postsynaptic cell ▪ The axon hillock constantly calculates the total amount of excitation and the total amount of inhibition; it integrates all the inputs o If the integrated number is high enough, the cell will be brought to threshold, and the voltage- gated Na channels will open and the cell will fire + an action potential. The action potential will then travel down the axon to the synaptic terminals. o If the integrated number is not high enough, the cell will not reach threshold and an action potential will not occur ▪ All of the inputs, both excitatory or inhibitory reaching the axon hillock at any given time, determine whether the cell hits threshold PSPs Summate (2 slides):  (These slides go through an integration problem. Key is that all the PSPs, either EPSPs or IPSPs, summate. This determines the change in membrane potential and whether a cell reaches threshold or not. EPSPs bring cells closer to threshold and IPSPs move cells further from threshold) Complexity of Behavior: ▪ Synaptic integration increases complexity of behavior ▪ The exact same stimulus in two different situations can generate two completely different responses; the reason for this is either an increase or decrease of inhibition of excitation of the different neurons within a pathway Comparison of PSPs and APs: ▪ It compares post-synaptic potentials and action potentials. ▪ Amplitude: o Post-synaptic potentials: small, depolarizing or hyperpolarizing o Action potentials: always the same size, only depolarizing (they are never hyperpolarizing), all- or-none (if the strength of the stimulus exceeds the threshold potential, the nerve will give a complete response; there is no response if threshold is not exceeded) ▪ Duration: o Postsynaptic potentials have a longer duration than action potentials (Action potentials ~ 2 to 3 milliseconds; Postsynaptic potentials ~ 10-20 milliseconds to a few seconds in duration) ▪ Location: o Postsynaptic potentials are mostly evoked on dendrites or the soma as this is where the synapse  is located between the presynaptic neuron and the postsynaptic neuron o Action potentials are initiated at the axon hillock or the initial segment of the axon and transmitted down the axon to the synaptic terminals ▪ Conduction: o Postsynaptic potentials are passive, travel short distances and decrease in amplitude as they travel o Action potentials are active, travel long distances and are regenerated at every point. In a myelinated axon, the action potentials are regenerated at every node of Ranvier back to their initial amplitude. In an unmyelinated axon, they remain at their initial amplitude due to the opening of the voltage-gated Na and K channels. + + ▪ Function: o Postsynaptic potentials function to change the electrical potential of the postsynaptic neuron, ❖ A depolarizing synapse with an excitatory neurotransmitter (glutamate)moves the potential closer to threshold ❖ A hyperpolarizing synapse with an inhibitory neurotransmitter (GABA or glycine) moves the potential further away from threshold ❖ Postsynaptic potentials trigger action potentials when the axon hillock is depolarized to the threshold value. o Action potentials are simply generated if threshold is reached and will travel to the synaptic terminals to initiate neurotransmitter release Lecture 6 recording 18: Muscle Neuron Structure and Integrity: ▪ This section looks at the efferent neuron, or motor neuron, of the quadriceps muscle and how an action potential travels down, releases neurotransmitter at the synaptic terminals and results in an actual physical muscle contraction 3 Types of Muscle (2 slides): (Only need to know the properties of skeletal muscle for this section. Other sections will look at cardiac muscle and smooth muscle) ▪ 3 types of muscle: skeletal muscle, cardiac muscle and smooth muscle ▪ Skeletal muscle: o Muscle attached to the skeleton o Also called striated muscle o Contraction is under voluntary control Skeletal Muscle: ▪ Each muscle consists of a number of muscle cells or muscle fibers which run lengthwise along the muscle ▪ Each muscle cell is surrounded by endomysium ( a membrane that sits over each muscle cell and electrically isolates the muscle cells from one another) Lecture 6 recording 19: The Motor Neuron and the Neuromuscular Junction Role of the Motorneuron: ▪ An efferent neuron, also called a motor neuron, innervates the quadriceps muscle ▪ Neurotransmitter is released at the synaptic terminals and results in muscle contraction  ▪ Motor unit → the motor neuron, its axon and all the muscle fibers it activates o The motor unit is the functional unit of the motor system and represents the smallest increment of force that can be generated in a muscle. ▪ Each muscle fiber only has one synapse, called the neuromuscular junction o Comparison: In the nervous system there are 10,000 to 40,000 synaptic inputs onto any post- synaptic cell. In the case of the motor neuron innervating muscle, the postsynaptic cell is the muscle fiber, and each muscle fiber has only one synapse Neuromuscular Junction: ▪ Neuromuscular junction (NMJ) → synapse between the efferent/motor neuron and the muscle fiber; do not directly make contact at the neuromuscular junction, but are separated by a small space, called the synaptic cleft or the synapse. o Muscle cell/muscle fiber is the postsynaptic cell ▪ Directly-gated chemical synaptic transmission occurs at the NMJ ▪ Motor end plate → region of the muscle fiber plasma membrane that lies directly under the terminal portion of the axon ▪ An action potential travels down the efferent neuron to the presynaptic terminal resulting in depolarization and the opening of voltage-gated calcium channels ▪ Calcium enters into the pre-synaptic terminal and causes the synaptic vesicles to fuse with the presynaptic membrane, releasing neurotransmitter into the synaptic cleft  ▪ Acetylcholine (ACH) is the neurotransmitter released by the efferent or motor neuron o An excitatory neurotransmitter ▪ ACH binds to nicotinic receptors located on the postsynaptic membrane o Ionotropic receptors -receptors that form ion channels following the binding of a ligand; ligand-gated ion channels ▪ Following the binding of ACH, the nicotinic receptors open and allow Na to enter the postsynaptic cell (the + muscle cell) o Na moving into the cell causes a local + depolarization o Muscle cells also have voltage-gated Na + channels along the membrane close to the synaptic terminals. ❖ The local depolarization will bring the muscle cell to threshold and open the voltage-gated Na channels, producing an + action potential in the muscle Neuromuscular Junction: ▪ Differences between synaptic transmission at NMJ and a central synapse: o One AP in motor neuron generates one AP in muscle cell (summation is required in the CNS) o Each muscle fiber (cell) is only innervated by one presynaptic axon o No inhibitory transmitters are released at NMJ (Acetylcholine = excitatory) Lecture 6 recording 20: Events at the Neuromuscular Junction Role of the Motorneuron (9 slides):  ▪ Muscle cell = postsynaptic cell ▪ One axon terminal/synaptic terminal synapses with one muscle cell/muscle fiber ▪ Axon terminals contain vesicles filled with neurotransmitter (ACH) ▪ At rest, muscle fiber is negatively inside with respect to extracellular space o Transverse tubule (T-tubule) is extracellular space and is positively charged with respect to the intracellular space ▪ An action potential travels down to the presynaptic terminal, causing the release of ACH by exocytosis into the synaptic cleft ▪ ACH binds to nicotinic receptors on the postsynaptic membrane, or the muscle cell, and Na enters into the + cell o The muscle cell/fiber is depolarized in the region under the synaptic terminal (motor end plate) due to entry of Na + o Current flows between this region and the adjacent membrane, which is currently at rest, depolarizing the adjacent membrane to threshold and opening voltage-gated Na channels + ▪ An action potential is generated due to Na entry + through the voltage-gated Na channels + ▪ The action potential propagates or travels along the surface of the muscle fiber, travelling outward in both directions toward the ends of the muscle fiber and down the transverse tubules (T-tubules) Lecture 6 recording 21: Excitation-contraction Coupling and Muscle Structure Excitation-contraction Coupling: ▪ Calcium:  o Important for calcium release o Stored in the sarcoplasmic reticulum ▪ How does an action potential travelling down the T- tubule result in the release of calcium needed for muscle contraction? o An action potential travels down the T- tubule and activates a voltage-gated Ca channel called 2+ the dihydropyridine or DHP receptor ❖ Main role of the DHP receptor: act as a voltage sensor, responding to changes in the membrane potential ❖ The DHP receptor is physically coupled to the ryanodine receptor through a foot process ✓ Ryanodine receptor is a large molecule that includes the foot process and also forms a calcium channel which is inserted in the membrane of the sarcoplasmic reticulum ✓ When the action potential travels down the T-tubule, it causes a conformational change in the DHP receptor. This conformational change acts through the foot process to open the ryanodine receptor channel located in the sarcoplasmic reticulum. ✓ Calcium rushes out of the sarcoplasmic reticulum into the cytosol of the muscle cell through the ryanodine receptor ✓ Calcium interacts with the contractile elements of the muscle cell underneath the sarcoplasmic reticulum Excitation-contraction Coupling: A Comparison  ▪ In the heart: the mechanism differs from that in skeletal muscle. There is no physical coupling in cardiac muscle but instead calcium-induced calcium release (more in cardiovascular section) Structure of a Muscle Cell: ▪ Muscle cell/fiber: o Has myofibrils comprised of the contractile elements, or the myofilaments, actin and myosin. ❖ Actin and myosin are protein filaments Structure of a Muscle Cell: ▪ Sarcomere: o A structural unit of a myofibril in striated muscle o Bound on either side by Z-lines (interconnecting networks of proteins) o Contractile elements are the myofilaments, which include the thick filaments and the thin filaments o Thick filaments are made of the protein myosin o Thin filaments are made primarily of the protein actin ❖ Thick filaments and thin filaments interact with each other and result in the actual shortening, or contraction, of the muscle Multiple Myofilaments: ▪ Although the sarcomere shortens, the length of each myofilament does not change; the width of the H zone changes Sarcomere Contraction: An Animation: (This is an animation showing sarcomere shortening. Important point: During muscle contraction the sarcomere shortens and the H zone becomes narrower) Lecture 7 recording 22: Molecular Participants in Skeletal Muscle Contraction Molecular Participants: ▪ Sliding Filament Theory: describes how a skeletal muscle contracts; involves 5 different molecules and calcium o Myosin → forms thick filaments o Actin → primary protein in thin filaments o Tropomyosin → regulatory protein binds to actin o Troponin → binds actin and tropomyosin, site of calcium binding o ATP → energy source to power muscle contraction o Calcium ions → released from the sarcoplasmic reticulum Myosin: ▪ Myofibril are made of sarcomeres, which are composed of the myofilaments, the thick and thin filaments ▪ Sarcomeres extend between two adjacent Z-lines ▪ In skeletal muscle cells, the myosin molecules are bundled together to form the thick filaments o Myosin molecules have a long tail with 2 globular heads attached to the tails ❖ The globular heads are called cross-bridges ❖ The heads (cross-bridges) have the ability to move back and forth ❖ The flexing movement of the head provides the “power stroke” for muscle contraction Myosin: ▪ The cross-bridge has two binding sites o One site binds ATP and the other site binds actin.  ❖ The binding site for actin is on the top of the globular head and the binding site for ATP is at the base of the globular head ▪ The myosin molecule can exist in two different states, a low energy state and a high energy state o In the low energy state the head of the myosin molecule is bent and myosin is bound to ATP o The myosin molecule switches between the low energy state to the high energy state by hydrolyzing a molecule of ATP o In the high energy state the head of myosin is bound to ADP and inorganic phosphate, and the position of the head has changed; the myosin head is now flat Thin Filament: ▪ Actin is the major component of the thin filament and has a binding site for myosin ▪ 2 other molecules are associated with the thin filaments are tropomyosin and troponin o Tropomyosin is a regulatory protein that is a double helical shaped strand which wraps itself around the actin filament and it covers up all of the myosin binding sites on the actin molecules ❖ In the unstimulated muscle, the position of the tropomyosin covers the binding sites on the actin subunits, preventing myosin cross- bridges from interacting with or binding with actin Thin Filament: ▪ Troponin is attached to the tropomyosin molecule at regular intervals o Troponin has a binding site for calcium o To expose the binding sites for myosin on actin,  tropomyosin must be moved aside; this is facilitated by troponin ❖ Calcium is released from the sarcoplasmic reticulum after an action potential and binds to its binding site on troponin. Troponin moves tropomyosin away from blocking the myosin binding sites on the actin molecule. Lecture 7 recording 23: Cross-bridge Cycling Six Step of Cross-bridge Cycling: ▪ Cross-bridge cycling is the cycle whereby myosin reaches up and grabs actin and causes the muscle to contract ▪ Muscle action potential propagated through the T- tubule system, causing the release of calcium from the sarcoplasmic reticulum into the cytosol. Calcium is released due to coupling of the dihydropyridine receptor (the voltage-gated Ca channel) with the 2+ ryanodine receptor. ▪ Six steps of cross-bridge cycling: (We will go over theses in detail in this section. This slide is a quick summary of the steps) Cross-bridge Cycling Overview: (We will look at the steps of cross-bridge cycling in more detail) Cross-bridge Cycling ▪ Step 1: o Exposure of the binding sites on the actin molecule. An action potential causes the release of calcium from the sarcoplasmic reticulum. Calcium floods into the cytosol of the muscle fiber. Calcium binds to troponin molecules on the thin filament and causes a conformational change in the troponin-tropomyosin complex, causing the  tropomyosin to be dragged away from the myosin binding sites on actin, exposing the myosin binding sites on actin. o Myosin must be in its high energy state to bind to its binding site on actin. In the high energy state, ATP has been hydrolyzed into adenosine diphosphate, or ADP, and inorganic phosphate; the energy from the hydrolysis of ATP puts the myosin head into its high energy state, a condition that prepares it for binding to actin. ▪ Step 2: o The myosin molecule binds to the myosin binding site on actin. The myosin cross-bridge is energized, or in its high energy state. ▪ Step 3: o The power stroke. The myosin head, which is bound to its binding site on actin, pivots forward. This pivoting of the head causes the H-zone to shorten, pushing the actin molecule to the middle of the sarcomere. In addition, during the power stroke the binding of myosin to actin causes a conformational change in the cross-bridge, which results in the release of ADP and inorganic phosphate from their binding site on the head of the myosin molecule. ▪ Step 4: o The myosin molecule, which is in its low energy state and bent forward, is released from the thin filament. ❖ In order for the myosin head to be released from the thin filament, a molecule of ATP must bind to its binding site at the base of the myosin head; this causes a conformational change, releasing the myosin  head from its binding site on actin. ▪ Step 5: o Re-energizing and repositioning of the cross- bridges. ❖ The myosin head is reset, ready to start a new cycle and generate more muscle contractions. ATP has bound to its binding site on the myosin head causing the release of the myosin cross-bridge from actin. The release of the myosin cross-bridge from actin triggers the hydrolysis of ATP into adenosine diphosphate and inorganic phosphate. Energy is transferred from ATP to the myosin cross-bridge. The myosin head is tilted up, back into its high energy state where it is bound to adenosine diphosphate and inorganic phosphate, ready to bind to actin again. o ATP is very important for muscle contraction: ❖ The binding of ATP is essential for the release of the myosin cross-bridge from its binding site on actin. ❖ The hydrolysis of ATP is essential for re- energizing and re-positioning the myosin molecule from its low energy state to its high energy state, to begin another cross- bridge cycle. ▪ Step 6: o Removal of calcium ions. The calcium ions that are bound to troponin are released and would move back into the sarcoplasmic reticulum by the action of ion pumps. o When the calcium ions are released from troponin, the troponin/tropomyosin complex  again covers the binding sites on actin ▪ At the neuromuscular junction, there is no inhibitory neurotransmitter; only acetylcholine is released and it is always excitatory. How then does muscle contraction stop or why do muscles ever stop contracting? o The reason for this is because of the absence of calcium ions Lecture 7 recording 24: More on the Cross-bridge Cycle Multiple Cross-bridge Cycles: ▪ At any given time, there are a large number of myosin molecules that are in the high energy state and ready to bind to actin. Depending on the task that you are doing, and depending on the amount of ATP that is present in your body, the number of myosin molecules that are ready to participate in contraction can be varied. o This will vary the intensity of the muscle contraction and also the duration of the muscle contraction ❖ The more ATP present, the more myosin molecules are energized and as a result, the longer the duration and the larger the amplitude of the muscle contractions ❖ The less ATP is present, the less myosin molecules that are in the high energy state and as a result, the shorter the duration and the smaller the amplitude of the muscle contractions ▪ During a contraction, all cross-bridges are neither bound nor disconnected at the same time Calcium Pumps: ▪ Calcium must move back into the sarcoplasmic  reticulum from the cytosol after muscle contraction is completed o Calcium is taken back up into the sarcoplasmic reticulum via an active transport pump present in the membrane of the sarcoplasmic reticulum ❖ This active transport pump requires ATP for activity Role of ATP: ▪ In the muscle cell the energy molecule ATP plays an important role in: o Energizing the power stroke of the myosin cross-bridge o Disconnecting the myosin cross-bridge from the binding site on actin at the conclusion of a power stroke o Pumping Ca back into the sarcoplasmic 2+ reticulum Lecture 7 recording 25: Types of Skeletal Muscle Fibers Metabolic Variations of Muscle Fiber Types: ▪ Two main types of muscle cells/muscle fibers: white muscle fibers and red muscle fibers o Differ in size and coloration o Differ in mechanisms for synthesizing ATP 4 slides: Features of White Muscle Fibers, Features of Red Muscle Fibers, Metabolism in White Muscle Fibers and Metabolism in Red Muscle Fibers ▪ Helpful things to know: o Myoglobin – the primary oxygen- carrying protein of muscle tissues o Capillaries – bring oxygen to the muscle cells o Mitochondria – require oxygen brought by blood capillaries to make ATP o Glycogen – the storage form of glucose; broken  down to release glucose o Glycolysis – uses glucose to make ATP in the absence of oxygen (anaerobic) This table summarizes the information in the 4 slides (Features of White Muscle Fibers, Features of Red Muscle Fibers, Metabolism in White Muscle Fibers and Metabolism in Red Muscle Fibers) Characteristic Red Muscle Fibers White Muscle Fibers Also called: Slow-twitch fibers Fast-twitch fibers Used for: Long-lasting continuous Intense but short-lasting contractions contractions Size: Half the diameter of white Large diameter muscle fibers Myoglobin: Large quantity of myoglobin Reduced myoglobin Blood supply: High blood supply (many Poor blood supply (few capillaries) capillaries) Mitochondria: Numerous mitochondria Few mitochondria Glycogen Content: Low glycogen content (do not High glycogen content rely solely on glucose to make (glycogen=storage form of ATP but use aerobic processes) glucose) Process used to make ATP: Krebs cycle and oxidative Glycolysis (anaerobic process - phosphorylation (aerobic does not require oxygen) processes - require oxygen) Speed of cross-bridge cycling Cross-bridge cycling occurs Rapid cross-bridge cycling relatively slowly results in fast contractions Fatigue Fatigue resistance and high Fatigue rapidly due to build-up endurance of lactic acid and glycogen Muscle Fiber Types: (This slide shows the proportion of red and white muscle fiber types in different people. You do not need to memorize this – it is simply for interest only) The Stretch Reflex: (This slide summarizes the stretch reflex and what we have learned about the neurons and the muscles involved) Lecture 1 recording 1: Basic Facts Facts About Blood: ▪ Blood → liquid connective tissue composed of different cells (red blood cells, white blood cells, platelets) dissolved in plasma. Blood also contains gases, waste products, nutrients, and hormones ▪ Blood is found in the circulatory system, in the blood vessels ▪ Blood is heavier or more viscous than water Functions of Blood: 1. Transport of substances in blood 2. Regulation of ion and pH balance 3. Defense and immune protection 4. Hemostasis or the prevention of blood loss Separation of Blood Cells and Plasma: ▪ Whole blood may be separated by centrifugation o Upper layer in test tube is plasma (makes 55% of blood volume) o Middle layer is called buffy coat; contains white blood cells and platelets (