Nervous Systems: Neuronal Cells: ⢠Electrically excitable ⢠Graded ...
Nervous Systems: Neuronal Cells: • Electrically excitable • Graded potentials are made of cell body and dendrites. • Action potentials are made of axon and presynaptic terminals. Order of Cells’ information propagation: 1. Dendrites: collects/receives electrical/nerurochemical signals. 2. Cell Body: integrates incoming signals and generates outgoing signals to axon through the axon hillock. 3. Axon: conducts electrical signals to the presynaptic terminals. 4. Presynaptic Terminals: transmits electrical signals to the next neuron, muscle, or gland. Depending on the environment the animals live in, the ionic composition of its body is varied. Thus, why extra cellular fluids =! Intercellular fluids. LOOK AT SLIDE. • Double Donnan Effect: The ECF is filled with many ions; the majority is Cl and so it is negatively charged. So, the ICF needs to balance out this electrochemical gradient, thus there are many negatively charged proteins to balance out this gradient. K+ is passively pumped into the ECF, while the Na+/K+ ATPase is pumping Na+ out and K+ in. This makes the plasma membrane a resistorcapacitor; resistance to the flow of charge and a capacitor by means of active and passive pumps. Also a positive charge in the ICF (due to excess K+ with proteins) and negative in the ECF (due to excess Cl and Na+) Resting membrane potential is calculated using the Nernst Equation and Goldman’s Equation: Nernst:
• • • • • •
Veq = equilibrium potential. This means that the specific ion will keep mving out until there’s a Veq mV of charge across the membrane. R = Gas constant = 8.31 T = temp in K. C K = C + 273.15 z = ionic charge (either /+ 1) F = Faraday’s constant = 96.4 [X] = ionic charges in the ECF and ICF. Because the plasma membrane is so thin, very few ions need to move to establish a gradient of great magnitudes.
Goldman:
•
Vm = membrane potential. None of the ions are at equilibrium at Vm.
•
P = membrane permeability. The concentrations are relatively fixed, so P is the determining factor. Ionic channels determine P. Depolarization & Hyperpolarization: Usually, the gradient is constant at ~ 70 mV (resting potential). When it is greater than 70 mV, it is considered depolarized. When it is less than 70 mV, it is considered hyperpolarized. • Depolarized: when Na+ channels are opened and Na+ rushes into the axon. ~2ms. • Hyperpolarized: when K+/Cl channels are opened and those ions move in. Graded Potentials: 1. Na+ channels open all around the dendrites, the cell depolarizes, reaches the axon hillock; the axon hillock reaches a certain threshold which determines whether it fires an action potential or not, then the axon hillock propagates the signal down the axon. 2. K+ and Cl opens all around the cell to repolarize it.
Decremental Potential: as you move away from the site of depolarization, it is less and less evident due to the active pumping of Na+ into the ECF and K+ into the ICF, through the Na+/K+ ATPase.
Action Potentials: Only an animal invention, NOT in fungi, etc. Lasts about 3 ms. • The ion channels are voltage gated. The ATPase is used in repolarization only. (FIRST PIC IN THE NEXT PAGE). A. Resting State: all channels except the passive K+ channels are closed. K+ is passively pumped into the axon.
B. Depolarization: K+ channel is closed and Na+ is open. Na+ rushes into the region of the axon. C. Repolarization: Na+ is pumped out of the cell through the ATPase. The K+ pump is opened, so K+ moves out of the axon. D. Hyperpolarization/Overshoot: All the channels are closed except the K+ pump, which is pumping K+ out of axon.
Propagation along the axon is mediated by lateral diffusion of the neighbouring Na+ channels. As the Na+ pumps in the depolarized regions are open to let Na+ in, the ATPases in the nondepolarized regions are actively pumping Na+ out of the axon. This creates a cycle of Na+ moving in and out quickly. FIRST PIC IN THE NEXT PAGE. The speed of the propagation is calculated using:
• E.g.
•
If you increase the diameter of the axon by increasing its volume, it neutralizes the effect; this is because as ions move in and out of the axon, due to the larger volume, it is harder to pump them out.
So through the evolutionary time, cells developed the myelin sheath (Schwann cells with large cytosols that wrap the axon of the neuronal cells). This increased the retention of ions by increasing rM.
•
o ONLY found in vertebrates (except hagfish and lampreys), though analogous ensheathments are found in some invertebrates. Most (if not all) pumps are placed in the Nodes of Ranvier. This is where all action potentials occur. This increases the speed at which the signals are propagated.
•
Without Myelin:
Chemical Synapses: • Slower than electrical synapses, but is unidirectional. Ca2+ is largely present between the pre and postsynaptic terminals. • Vesicles in the presynaptic terminal are bound to synapsin (protein that has a high affinity to the vesicles when not phosphorylated). 1. Ca2+ channels open up in the presynaptic terminal. This initiates the phosphorylation of synapsin. 2. Once phosphorylated, the synapsin loses its affinity to the vesicles carrying the neurotransmitters and releases it. Through exocytosis, the neurotransmitters are released. 3. The neurotransmitters bind to the receptors in the postsynaptic terminals, which initiates Na+ channels to open and Na+ movement into the cell to initiate another action potential through depolarization. The vesicles are recycled. Types of receptors on the postsynaptic cleft: • Ionotropic: neurotransmitters bind, channels open, then ions flow across the membrane into the cell. • Metabotropic: neurotransmitters bind to receptors, activates the Gprotein that’s attached to the receptor, then Gprotein subunits/intracellular messengers modulate the ion channels. Neurotransmitters: 1. Synthesized in neurons BEFORE being released, except soluble gasses. 2. Released from presynaptic cell, following depolarization. 3. Bind to postsynaptic receptor. 4. Cause a detectable effect in the postsynaptic neuron. • Many of these are nonessential amino acids, hormones, and synthesized on demand. SEE NEXT PAGE.
Neuropeptide Y
•
Termination occurs by recycling: reuptake by transporters, breakdown by ases on the postsynaptic cell, etc.
Muscles & Movement 1: 2 types, only 1 emphasized. 1. Striated: has alternating dark and light pattern. The actin and myosin is arranged in a regular way. Emphasized. 2. Smooth: the actin and myosin are not arranged in a pattern. Muscle Anatomy: LOOK AT PG 3 OF SLIDES. • Muscles are covered with epimysium, which are continuous with tendons. o Order of occurrence from the outside to the in: muscle fascicle (bands of myofibers that are covered by perimycium), myofiber (bands of myofibrils that are covered by endomysium), myofibril (bands of myofilaments that are covered by sarcoplasmic reticulum and sarcolemma), and myofilament (made of actin and myosin). FActin (Thin Filaments): made of Gactin and alpha actin, globular monomers of F Actin. • The length of Factin must be precisely regulated. This is done through capping proteins: pointed – slow growing end (tropomodulin protein) and barbed – fast growing end (capZ protein). If want to decrease the length, tropomodulin comes off and a protein cleaves it off; if want to increase the length, capZ comes off and is regulated by other proteins. • Have special regions in which myosin heads can bind to. Myosin II (Thick Filaments): made of a head, neck, and tail group. • Head (Heavy Chain): binds to actin in a certain region and has the ATP pocket to mark the release. • Neck (Light Chain): top of neck provides structural stability, while the bottom provides supplemental regulation of actinmyosin binding. • Arranged in such a way as to have the heads facing outwards while the tails inwards towards one another. LOOK at slide 6. Organization of the contractile elements in the skeletal muscles: striated. LOOK AT SLIDE 7. • Ibands (lighter): myosin is absent, made of actin, titin, nebulin, tropomodulin, capZ (AKA Zdisk made of alpha actinin in the middle of Iband where actin is anchored). Telethionin also present where titin is anchored to.
• •
Abands (darker): titin absent and capZ, made of all stated above, Hzone (AKA Mline in the middle where actin is absent and site where myosin is anchored). Sarcomere: a region from one Zdisk to the next. For every 1 thick filament, 6 thin filaments are arranged in a ‘flower’ fashion.
Muscle Contraction: Sliding Filament Theory (1954): Hugh Huxley with Jean Hanson and R. Niedergerke with Andre Huxley proposed this theory separately. • It states that there’s no change in length of filaments during contractions, only the overlapping of filaments in a sarcomere. Ibands become smaller and Hzone is lost. CrossBridge Cycling: A Cycle that Repeats. 1. Myosin head (+ ADP + Pi) binds to actin. At its low energy conformation. 2. As Pi is released, the head pulls the actin towards the middle of the sarcomere. Then ADP is released and it achieves its lowest energy state. 3. ATP binds to the myosin head, unbinding it from actin. This causes conformational change to actinbinding site of myosin. 4. The myosin head uses the energy of ATP hydrolysis to cock itself into a high energy state. • Not known for sure why there are two heads on a myosin, but two generates twice as much force as one headed myosin. LengthTension Relationship: • Supports the sliding filament theory. • Optimal Length = Active Tension = (Total Tension – Passive Tension) 1. Optimal Tension: as long as the myosin head grabs onto the right actin, we should be able to generate more force. 2. Suboptimal Tension: when you don’t get the most out of binding due to: A. Steric hindrance, wrong binding, Zdisk crashing. The myosin grabs onto the wrong actin (one in the other side). Limited by the Zdisk. Actin rams into other actin along the way, causing steric hindrance. B. No overlap. Thus, no tension. TroponinTropomyosin Complex (TTC): 1. Troponin T (TnT): links the troponin complex to the tropomyosin. 2. Troponin I (TnI): binds either to actin or TnC, depending on the [Ca2+]. 3. Troponin C (TnC): regulates its affinity to TnI. If [Ca2+] = low then Ca2+ sites are empty, thus weak interaction with TnI; vise versa.
•
IFF the [Ca2+] are high enough, the Ca2+ sites are filled at TnC, which increase its interaction with TnI and decreasing the interaction of TnI with actin. Thus it ‘rolls’ away from the actin’s myosin binding site. Calcium Storage: • To prevent muscle contraction [Ca2+] levels are to be kept really low one contraction. 2. Asynchronous Muscle: action potentials simply ‘turn muscles on’ (keeps Ca2+ levels high). • Several muscle contractions result from a single action potential. I.e. beetle. o Stretchactivation in effect. The longitudinal and vertical muscles contract in order. The stretch of one muscle activates the other. o LOOK AT FIRST PIC ON NEXT PAGE. • Have an additional mechanism where the myosin interacts with the troponin complex, which loses its affinity to actin. • No Ca2+ cycling = more space for myofilaments. This decreases the number of mitochondria and SR. In turn provides more power and speed.
Molluscan Catch Muscles: • Have smooth adductor muscles (catch muscles) that have twitchin protein that causes a contraction without ATP use. Keeps the shell together. • Also have striated adductor muscles (scallop meat). • Twitchin (2009): regulated by Ca2+ dependent phosphatase and cAMP – stimulated protein kinase A (release of cAMP is induced by serotonin). o Even though [Ca2+] is decreasing, contraction is staying the same, due to an enzyme that clips off phosphates.
• • • • • •
Veq = equilibrium potential. This means that the specific ion will keep mving out until there’s a Veq mV of charge across the membrane. R = Gas constant = 8.31 T = temp in K. C K = C + 273.15 z = ionic charge (either /+ 1) F = Faraday’s constant = 96.4 [X] = ionic charges in the ECF and ICF. Because the plasma membrane is so thin, very few ions need to move to establish a gradient of great magnitudes.
Goldman:
•
Vm = membrane potential. None of the ions are at equilibrium at Vm.
•
P = membrane permeability. The concentrations are relatively fixed, so P is the determining factor. Ionic channels determine P. Depolarization & Hyperpolarization: Usually, the gradient is constant at ~ 70 mV (resting potential). When it is greater than 70 mV, it is considered depolarized. When it is less than 70 mV, it is considered hyperpolarized. • Depolarized: when Na+ channels are opened and Na+ rushes into the axon. ~2ms. • Hyperpolarized: when K+/Cl channels are opened and those ions move in. Graded Potentials: 1. Na+ channels open all around the dendrites, the cell depolarizes, reaches the axon hillock; the axon hillock reaches a certain threshold which determines whether it fires an action potential or not, then the axon hillock propagates the signal down the axon. 2. K+ and Cl opens all around the cell to repolarize it.
Decremental Potential: as you move away from the site of depolarization, it is less and less evident due to the active pumping of Na+ into the ECF and K+ into the ICF, through the Na+/K+ ATPase.
Action Potentials: Only an animal invention, NOT in fungi, etc. Lasts about 3 ms. • The ion channels are voltage gated. The ATPase is used in repolarization only. (FIRST PIC IN THE NEXT PAGE). A. Resting State: all channels except the passive K+ channels are closed. K+ is passively pumped into the axon.
B. Depolarization: K+ channel is closed and Na+ is open. Na+ rushes into the region of the axon. C. Repolarization: Na+ is pumped out of the cell through the ATPase. The K+ pump is opened, so K+ moves out of the axon. D. Hyperpolarization/Overshoot: All the channels are closed except the K+ pump, which is pumping K+ out of axon.
Propagation along the axon is mediated by lateral diffusion of the neighbouring Na+ channels. As the Na+ pumps in the depolarized regions are open to let Na+ in, the ATPases in the nondepolarized regions are actively pumping Na+ out of the axon. This creates a cycle of Na+ moving in and out quickly. FIRST PIC IN THE NEXT PAGE. The speed of the propagation is calculated using:
• E.g.
•
If you increase the diameter of the axon by increasing its volume, it neutralizes the effect; this is because as ions move in and out of the axon, due to the larger volume, it is harder to pump them out.
So through the evolutionary time, cells developed the myelin sheath (Schwann cells with large cytosols that wrap the axon of the neuronal cells). This increased the retention of ions by increasing rM.
•
o ONLY found in vertebrates (except hagfish and lampreys), though analogous ensheathments are found in some invertebrates. Most (if not all) pumps are placed in the Nodes of Ranvier. This is where all action potentials occur. This increases the speed at which the signals are propagated.
•
Without Myelin:
Chemical Synapses: • Slower than electrical synapses, but is unidirectional. Ca2+ is largely present between the pre and postsynaptic terminals. • Vesicles in the presynaptic terminal are bound to synapsin (protein that has a high affinity to the vesicles when not phosphorylated). 1. Ca2+ channels open up in the presynaptic terminal. This initiates the phosphorylation of synapsin. 2. Once phosphorylated, the synapsin loses its affinity to the vesicles carrying the neurotransmitters and releases it. Through exocytosis, the neurotransmitters are released. 3. The neurotransmitters bind to the receptors in the postsynaptic terminals, which initiates Na+ channels to open and Na+ movement into the cell to initiate another action potential through depolarization. The vesicles are recycled. Types of receptors on the postsynaptic cleft: • Ionotropic: neurotransmitters bind, channels open, then ions flow across the membrane into the cell. • Metabotropic: neurotransmitters bind to receptors, activates the Gprotein that’s attached to the receptor, then Gprotein subunits/intracellular messengers modulate the ion channels. Neurotransmitters: 1. Synthesized in neurons BEFORE being released, except soluble gasses. 2. Released from presynaptic cell, following depolarization. 3. Bind to postsynaptic receptor. 4. Cause a detectable effect in the postsynaptic neuron. • Many of these are nonessential amino acids, hormones, and synthesized on demand. SEE NEXT PAGE.
Neuropeptide Y
•
Termination occurs by recycling: reuptake by transporters, breakdown by ases on the postsynaptic cell, etc.
Muscles & Movement 1: 2 types, only 1 emphasized. 1. Striated: has alternating dark and light pattern. The actin and myosin is arranged in a regular way. Emphasized. 2. Smooth: the actin and myosin are not arranged in a pattern. Muscle Anatomy: LOOK AT PG 3 OF SLIDES. • Muscles are covered with epimysium, which are continuous with tendons. o Order of occurrence from the outside to the in: muscle fascicle (bands of myofibers that are covered by perimycium), myofiber (bands of myofibrils that are covered by endomysium), myofibril (bands of myofilaments that are covered by sarcoplasmic reticulum and sarcolemma), and myofilament (made of actin and myosin). FActin (Thin Filaments): made of Gactin and alpha actin, globular monomers of F Actin. • The length of Factin must be precisely regulated. This is done through capping proteins: pointed – slow growing end (tropomodulin protein) and barbed – fast growing end (capZ protein). If want to decrease the length, tropomodulin comes off and a protein cleaves it off; if want to increase the length, capZ comes off and is regulated by other proteins. • Have special regions in which myosin heads can bind to. Myosin II (Thick Filaments): made of a head, neck, and tail group. • Head (Heavy Chain): binds to actin in a certain region and has the ATP pocket to mark the release. • Neck (Light Chain): top of neck provides structural stability, while the bottom provides supplemental regulation of actinmyosin binding. • Arranged in such a way as to have the heads facing outwards while the tails inwards towards one another. LOOK at slide 6. Organization of the contractile elements in the skeletal muscles: striated. LOOK AT SLIDE 7. • Ibands (lighter): myosin is absent, made of actin, titin, nebulin, tropomodulin, capZ (AKA Zdisk made of alpha actinin in the middle of Iband where actin is anchored). Telethionin also present where titin is anchored to.
• •
Abands (darker): titin absent and capZ, made of all stated above, Hzone (AKA Mline in the middle where actin is absent and site where myosin is anchored). Sarcomere: a region from one Zdisk to the next. For every 1 thick filament, 6 thin filaments are arranged in a ‘flower’ fashion.
Muscle Contraction: Sliding Filament Theory (1954): Hugh Huxley with Jean Hanson and R. Niedergerke with Andre Huxley proposed this theory separately. • It states that there’s no change in length of filaments during contractions, only the overlapping of filaments in a sarcomere. Ibands become smaller and Hzone is lost. CrossBridge Cycling: A Cycle that Repeats. 1. Myosin head (+ ADP + Pi) binds to actin. At its low energy conformation. 2. As Pi is released, the head pulls the actin towards the middle of the sarcomere. Then ADP is released and it achieves its lowest energy state. 3. ATP binds to the myosin head, unbinding it from actin. This causes conformational change to actinbinding site of myosin. 4. The myosin head uses the energy of ATP hydrolysis to cock itself into a high energy state. • Not known for sure why there are two heads on a myosin, but two generates twice as much force as one headed myosin. LengthTension Relationship: • Supports the sliding filament theory. • Optimal Length = Active Tension = (Total Tension – Passive Tension) 1. Optimal Tension: as long as the myosin head grabs onto the right actin, we should be able to generate more force. 2. Suboptimal Tension: when you don’t get the most out of binding due to: A. Steric hindrance, wrong binding, Zdisk crashing. The myosin grabs onto the wrong actin (one in the other side). Limited by the Zdisk. Actin rams into other actin along the way, causing steric hindrance. B. No overlap. Thus, no tension. TroponinTropomyosin Complex (TTC): 1. Troponin T (TnT): links the troponin complex to the tropomyosin. 2. Troponin I (TnI): binds either to actin or TnC, depending on the [Ca2+]. 3. Troponin C (TnC): regulates its affinity to TnI. If [Ca2+] = low then Ca2+ sites are empty, thus weak interaction with TnI; vise versa.
•
IFF the [Ca2+] are high enough, the Ca2+ sites are filled at TnC, which increase its interaction with TnI and decreasing the interaction of TnI with actin. Thus it ‘rolls’ away from the actin’s myosin binding site. Calcium Storage: • To prevent muscle contraction [Ca2+] levels are to be kept really low one contraction. 2. Asynchronous Muscle: action potentials simply ‘turn muscles on’ (keeps Ca2+ levels high). • Several muscle contractions result from a single action potential. I.e. beetle. o Stretchactivation in effect. The longitudinal and vertical muscles contract in order. The stretch of one muscle activates the other. o LOOK AT FIRST PIC ON NEXT PAGE. • Have an additional mechanism where the myosin interacts with the troponin complex, which loses its affinity to actin. • No Ca2+ cycling = more space for myofilaments. This decreases the number of mitochondria and SR. In turn provides more power and speed.
Molluscan Catch Muscles: • Have smooth adductor muscles (catch muscles) that have twitchin protein that causes a contraction without ATP use. Keeps the shell together. • Also have striated adductor muscles (scallop meat). • Twitchin (2009): regulated by Ca2+ dependent phosphatase and cAMP – stimulated protein kinase A (release of cAMP is induced by serotonin). o Even though [Ca2+] is decreasing, contraction is staying the same, due to an enzyme that clips off phosphates.
