PSL 300 Finals Notes PDF

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PSL 300 FINALS NOTES Lecture 1: Cell Membrane:  Cell membrane is not an inert bag holding the cell together  Cell membrane is composed of phospholipid bilayer  Lipid-soluble molecules and gases diffuse through readily  Water-soluble molecules cannot cross without help  Proteins are large so are impermeable to organic anions  Permeability depends on molecular size, lipid solubility, and charge  Polar molecules and ions need help of proteins to cross Simple Diffusion:  Small lipid-soluble molecules and gases pass either directly through the phospholipid bilayer or through pores  Movement of substrate is down concentration gradient  Relative rate of diffusion is roughly proportional to the concentration gradient across the membrane  Passive: no energy input required from ATP Facilitated Diffusion:  Molecule diffuse across membrane with the assistance of carrier protein o Aids in movement of polar molecules across cell membrane  Movement of substrate is down concentration gradient  Energy comes from concentration gradient of the solute  Passive: no energy input required from ATP Active Transport:  Move selected molecules across cell membranes against their concentration gradient  Substrate binds to protein carrier that changes conformation to move substrate across membrane  Requires energy from ATP hydrolysis  ATPases (Na+/K+ pump) Secondary Active Transport:  Not directly using ATP; relies on kinetic energy  When a substance is carried up its conc. gradient without ATP catabolism  Kinetic energy of movement of one substance down conc. gradient powers the simultaneous transport of another up its conc. gradient  Do not require ATP themselves  Induces conformational change in protein  Powered by chemical energy in the ion diffusing down conc. Gradient and this energy is used to push some solutes against conc. Gradient Channels:  Membrane spanning protein forms a pore right through membrane through which specific ions can diffuse through  Pore loops of protein molecules dangle inside the channel  Pore loop creates selectivity filter where only specific molecules can diffuse through o Aka membrane channels  Gated channels: not kept perpetually open; gate is closed and no diffusion takes place under certain conditions

o Protein components switch between 2 shapes; one creates an open pore and the other blocks the pore  Ligand gated channels: binding of chemical agent o Part of the body’s chemical signaling system o Binding of receptor triggers events at the membrane such as activation of an enzyme  Voltage gated channels: change in voltage across the membrane changes conformation of channel  diffusion pore o Voltage sensing mechanism is in the 4th transmembrane domain (S4 segment) o S4 wing has amino acids with +ve charges on it  Natural position is in upward position but because of +ve charges on outside of cell and -ve charges inside cell, the wings get pushed down  Depolarization of membrane to about -50mV no longer provides sufficient electrical attraction to hold the S4 wing down so wings migrate up  no more structural occlusion from pore so ions can now diffuse through Endocytosis/exocytosis:  Both involves vesicles (specialized compartments that carry molecule of interest)  Endocytosis: inward pinching of membrane to create vesicle; from outside to inside  Exocytosis: partial or complete fusion of vesicle with cell membrane for bulk transmembrane transport of specific molecules; from inside to outside o Exocytosis 1: more rapid mechanism; Kiss and Run  Secretory vesicles dock and fuse with plasma membrane at fusion pore  Vesicles connect an disconnect several times before contents are emptied  Used for low rate of signaling  Contents are only partially emptied each time o Exocytosis 2: full exocytosis; full fusion  Total release of vesicle contents at once  High levels of signaling; lots of content  Must be counterbalanced by endocytosis to stabilize membrane surface area Membrane Potential:  All cells in body generate membrane potential, not just neurons  MP: electric potential difference between inside and outside of a cell  2 conditions to generate MP o Create a concentration gradient: an enzyme ion pump must actively transport certain ion species across the membrane to create conc. Gradient  Different distribution of ions where ion conc. is higher on one side o Semi-permeable membrane: allows one ion species to diffuse across the membrane more than others Na+/K+ Pump:  All cell membrane is loaded with Na+/K+ pumps  Na+, K+ dependent ATPase: enzyme that moves 3 Na+ and 2 K+ into cell by breaking down ATP  creates conc. gradient  Consumes 1/3 of energy needs of body; 2/3 in neurons

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Na/K inequality  potential difference of -10mV making inside of cell more positive o Higher sodium conc. outside of cell o Higher potassium conc. inside cell Resting Membrane Potential:  Resting MP is closer to -70mV  Resting membrane is most permeable to K+ ions  K+ diffuses out of cell down conc. gradient through K+ channels  Cations accumulate on outside of membrane leaving inside of cell to be net -ve  Efflux occurs until there is a buildup of +ve charges on the outside of membrane that further diffusion of K+ is repelled by electromagnetic force = equilibrium K+ Channel:  2 pores within the structure through which only K ions can pass; KCNK channel where K+ leaks Nernst Equation:  Equilibrium: electrical work to repel outward cation diffusion = chemical work of diffusion down conc. gradient  Membrane potential at equilibrium is determined by conc. gradient  Nernst equation: the balance between chemical work of diffusion with electrical work of repulsion o Result is only valid if only one ion species is diffusing across the membrane o EK+ = (RT/F) ln([K+]o/[K+]i) = -90mV  MP if only K+ ions was involved o BUT resting MP is not -90 meaning K doesn’t get its way Lecture 2: Goldman Equation:  Membrane is most permeable to K+ at rest but Na+ and Cl- ions also contribute  Goldman equation: puts all ion species into consideration for overall membrane potential o Em calculated to be -70mV

Na+ Equilibrium Potential:  Under certain circumstances, the permeability of Na+ can be dominant change MP drastically  If only permeable to Na+ , there is more Na+ on the outside causing net influx of Na into cell bring more positive charges so there is net cation accumulation  Membrane potential is +ve inside with respect to outside  ENa+ = +60mV  Influx of Na+ doesn’t happen forever because Na+ is carrying a +ve charge so until there is buildup of positive charges inside of cell membrane, Na+ gets repelled by electromagnetic force  no more net movement of Na+ across membrane Cl- ions:  There are large proteins inside cells and most of them have -ve charges so Cl- ions are pushed out of cell since large proteins can’t get out unless through exocytosis  Therefore, Cl- ions are more concentrated on the outside Na+ Channels:

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Membrane increase conductance by opening a channel (voltage-gated Na+ channel) only permeable to Na+ ions to generate AP  Normal resting MP, Na+ channel is shut so need to depolarize membrane to open Na+ channel  Channel normally is closed at -70mV at rest  Na+ channel is opened by depolarizing membrane to -55mV  Massive influx of Na+ but inactivation gate swings shut shutting down process about ½ms after opening of Na+ channel  To remove inactivation, MP needs to fall below threshold again Action Potential:  Can only produce an AP in membrane that contains voltage-gated Na+ channels  When channels are open, MP surges towards ENa+ = 60mV  Resting membrane potential  Depolarizing stimulus  Membrane depolarizes to threshold  Voltage-gated Na+ and K+ channels begins to open  Rapid Na+ entry depolarizes cell  Na+ channels close and slower K+ channels open  K+ moves from cell to ECF  K+ channels remain open and additional K+ leaves cell, hyperpolarizing it  Voltage-gated K+ channels close, less K+ leakage  Cell returns to resting ion permeability and resting MP  Na+/K+ ATPase still active during AP  always working and maintaining conc. gradient  Whole AP lasts about 2ms Threshold:  Threshold: minimal signal required to generate AP  Subthreshold stimuli: not that strong; induces change in MP but not strong enough for full AP  Threshold stimulus: stronger and is strong enough to bring potential up to -55mV  Suprathreshold stimulus: stimulated AP but AP is not any bigger than threshold stimulus (all/none principle)  Frequency coding: longer/stronger stimulus can increase frequency of AP o 10ms vs 20ms threshold stimulus  20ms stimulus might generate 2 Aps Refractory Periods:  Period in which all or some Na+ channels are inactivated/unavailable for generation of second AP  Na+ channels remain inactivated until MP drops below threshold  channels reconfigure to original state and membrane becomes excitable again  Absolute RP: no channels are reconfigured  no stimulus (limiting factor) o Excitability of membrane is 0  unable to fire another AP  Relative RP: some but not all channels are reconfigured o The longer you wait, more voltage gated Na+ channels become available, so size of AP becomes bigger o Successive stimuli can have AP but might not be as high strength Depolarization Block:  Keep membrane depolarized to completely block AP

o Na+ channels permanently inactivated so unable to generate AP  Destroy conc. gradient for K+ because K+ is responsible for keeping MP at -70mV  Introduce more K+ into extracellular space (ex. KCl injection)  difficult for K+ to leave cell because higher conc. outside so hard to maintain MP at -70mV  membrane remains in absolute refractory state  inexcitable After-Hyperpolarization:  K+ channels have much slower kinetics than Na+ channels so they open gradually  max outward K+ current occurs AFTER Na+ inactivation  Want this channel to act later to bring MP back down to resting levels  “extra” K+ channels and leakage K+ channels = greater outward K+ current  MP = more polarized = more -ve = hyper-polarization Lecture 3: Impulse Conduction + Excitable Cells:  Once started, AP will propagate from origin across rest of cell until it reaches the end of an axon/dies out  Most cells are not ‘excitable’ because they lack voltage-gated Na+ channels but will conduct passive currents  Axon: long extension of cell body that carry AP away to some other location  Synapse: the region where an axon terminal communicates with its postsynaptic target cell  If we put voltage across membrane on one location and measure voltage across membrane some distance away, it doesn’t look like anything we started with  losing signal as current travels along membrane o Biological tissue is bad conductor Cable Properties:  Length constant : measure how quickly a potential difference disappears as a function of distance o Conduction of velocity of an AP along an axon depends on  o Bigger  = longer distance the impulse can be carried  2 ways to increase : o Increasing diameter (larger diameter = less internal resistance = less voltage lost across resistance as current travels through) o Increasing membrane resistance (higher membrane resistance = less current leaked out = current forced down membrane)   defined with internal resistance, extracellular fluid resistance and membrane resistance o ECF resistance is low, it is dropped from equation   = √ R m /(R o+ R i)   = √ R m / R i   = the distance you can travel to the point where the voltage drops about 37% of its original value  Want to increase  as much as possible to depolarizing current will spread a great distance Myelination:  Increases membrane resistance and is most efficient in increasing conduction velocity

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Glial cells: assist nervous system and is required for nutrition and increased membrane resistance  Specialized glial cells (schwann cells (PNS)/ oligodendrocytes (CNS)) wrap around successive sections of an axon  myelin sheath  50-100 layers wrapping around axon  increases membrane resistance  reduces leakage o Wraps around important axons but can’t afford to wrap around many times for all axons because it gets too bulky  only 20% of axons are myelinated o Small gaps left between adjacent glial cells = Node of Ranvier  Huge conc. of voltage gated channels and the only place where AP can be generated  Multiple sclerosis: compromise of myelin sheath resulting in difficulty conducting impulse Saltatory Conduction:  AP needs to jump from one place to the next since only membrane exposed at nodes is excitable  Depolarizing current generated at one site is strong enough to travel down axon for many nodes bringing 5-10 nodes to -50mV generating Aps on all the next nodes  Myelin prevents leakage of current across membrane between nodes  Only the furthest node counts (10th node) because it is now the depolarizing force for the next 10 nodes o When node 11 is just activated, node 1 is done AP  Safety factor: if one node is damaged, the depolarizing current will just skip past and move on to next healthy node o Need extensive damage before AP can be stopped in its tracks Node of Ranvier:  There is high density of voltage-gated Na+ channels  Only Na+ channels present at nodes!!! Unmyelinated Axons:  Get lots of current leakage and slows down conductance velocity  Slow conduction velocity  Both Na+ and K+ voltage-gated channels are intermixed  Majority of axons are unmyelinated  Do have some insulation  schwann cell and oligodendrocytes engulf the axon o Remak Bundle Axon Terminal:  AP conducted along membrane to the end of cell so why does depolarizing current not go backwards? o AP cannot turn around and repropagate in direction is came from because of refractory period  Na+ channels are inactivated Synapses:  Functional association of a neuron with another neuron or effector organs  Electrical synapse: adjacent membranes are about 35A apart o Gap junctions are bridged by connexins allowing small ions to cross o Useful for rapid communication because it is just a channel connecting 2 cells together

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Chemical synapse: transmitter released into extracellular space o Defined by a presynaptic surface (bouton containing the vesicles) and postsynaptic membrane (membrane of adjacent neuron) o Synaptic cleft is about 200A wide o Space is specialized due to existence of postsynaptic membrane containing specific protein receptors that bind to transmitters released  AP depolarized the axon terminal  Depolarization opens voltage-gated Ca2+ channels and Ca2+ enters cell  Calcium entry triggers exocytosis of vesicle contents  Neurotransmitters diffuse across synaptic cleft and binds with receptors on postsynaptic cell  initiating a response  Chemical synapses are processing stations; 1 AP has 10-90% chance of releasing 1 vesicle  not all vesicles will fuse with membrane and release neurotransmitter Vesicle Release:  Triger for exocytosis is always Ca2+ ions  AP depolarizes bouton membrane  reaches threshold @ -50mV  Ca2+ diffuses into bouton and triggers cascade of reactions  Vesicles are usually docked in preparation for fusion  Ca2+ interacts with SNARE proteins allowing fusion of vesicle membrane Lecture 4: Post Synaptic Receptors:  Binding of transmitter causes a change in shape of the receptor protein  Receptors are either: o Ionotropic: ligand binding opens an ion channel  PSP  Duration is about 20-40ms; will continue as long as neurotransmitter is present  Ion channel may be specific for cations (Na+/K+); EPSP (depolarizing)  inside of cell becomes more +ve  Or specific for Cl-/K+ ions; IPSP (hyperpolarizing)  inside of cell becomes more -ve  Ex. Nicotinic receptor for acetylcholine  Channel is part of receptor for ionotropic effects are fast  Ligands for ionotropic receptors: acetylcholine (Ach), glutamate, GABA, glycine  all generate IPSP o Metabotropic: ligand binds activating an enzyme that is usually G-protein coupled  results in increased/decreased production of 2nd messengers  2nd messengers are either cAMP, cGMP, or InP3  Takes time and is not necessary that there is change to MP  But can influence ion channel through metabolic effect but is slow because has to go through all the enzyme activity first before influencing ion channels  Ex. -adrenoreceptor for noradrenalin/norepinephrine; NA binds to receptor activating adenylyl cyclase through G-protein alteration  produces more cAMP  activates kinases phosphorylating Ca2+ channels  influx of Ca2+

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-blockers block activation of -receptors  drugs are taken by patients with heart problems to prevent overworking the heart  Ligands for metabotropic receptors: muscarinic receptor, ADH, catecholamines, serotonin, purines, gases  Receptors determines effect, not the transmitter  Neurotransmitters can bind to different receptors, but which receptor gets activated is important in determining what’s going to happen to post-synaptic neuron Spread of PSPs:  PSPs generated in inexcitable membrane so cannot initiate an AP  Nearest excitable membrane is at beginning of axon: trigger zone  PSP must spread through passive conduction across the membrane to get to the initial segment of axon PSP Summations:  There is loss of current as you go along membrane before reaching trigger zone o 1mV generated at dendrite  left with only ½mV by the time it reaches trigger zone o Need a lot of EPSPs added together to depolarize trigger zone to -50mV o Need summation  Spatial summation: minimum of 10-30 synchronous EPSPs in dendritic tree each from different synapses o Large number of EPSPs occurring at the same time o 3 excitatory neurons (graded potentials are all below threshold) fire o All arrive at trigger zone together and sum to create a suprathreshold signal o AP is generated  Temporal summation: generating EPSPs at high frequency but only need a few synapses o EPSPs last for about 30-40ms so successive inputs on any given synapse can generate subsequent EPSPs that add on to pre-existing EPSPs  On average, >50% of EPSP amplitude reaches trigger zone; loses about ¼ of signal as it travels down to trigger zone Inhibitory Post-Synaptic Potential:  IPSPs tend to be located halfway between the site where EPSP is generated and trigger zone  IPSPs have strategic advantage  can shunt depolarizing EPSP currents out of cell  Ex. Cl- channels: equilibrium is close to resting MP so at rest, opening this channel would have little change o When membrane is depolarized, opening this channel will bring MP back down to -70mV o IPSPs clamps MP preventing excitation  inhibitory effect Spike Train:  Spike train: powerful input translated into continuous stream of APs  After each spike, need membrane to be hyperpolarized to restore the Na+ channels to re-open them for the next one  Must have hyperpolarization to generate another AP or won’t get spike train  Need to overcome depolarization block  Voltage gated K+ channels at trigger zone cases afterhyperpolarizations

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After hyperpolarization fades away, MP will be able to shoot right back up where EPSP takes it and crosses the threshold again to form a new spike  repeats until EPSP fades away  NEED AFTERHYPERPOLARIZATION FOR SPIKE TRAIN Pre-synaptic Inhibition:  Release of GABA onto bouton opens GABA-gated Cl- channels  influx of Cl Prevents opening of voltage-gated Ca2+ channels  no exocytosis of vesicles  presynaptic inhibition of synaptic connection  Excitatory neuron fires  AP generated  Inhibitory neuron fires blocking neurotransmitter release at one synapse but has no effect on other synaptic connections  good for regulating information flow Lecture 5: Receptor Potential:  Change in MP due to receipt of signal from exterior sensory cue  Receptor proteins are embedded in sensory cell membrane  will change shape when specific energy is received  Can either directly open ion channels or activate enzymes through G-protein coupling  Chemical stimulus binds to specific metabotropic receptor  activation of G-protein  activate adjacent enzyme (adenylyl cyclase)  activated 2nd messenger (cAMP)  cAMP activate kinases  directly interact with ion channels/phosphoryla...