1
Q
Cell Membrane
A
- Composed of lipid bilayer
- Lipid soluble molecules + gases diffuse readily
- Water soluble(polar) molecules cannot cross without help
- Impermeable to proteins
2
Q
Simple Diffusion
A
- Small, non-polar molecules pass directly through lipid bilayer/pores
- Movement down concentration gradient(high to low)
- Passive(No ATP)
3
Q
Facilitated Diffusion
A
- Molecules diffuse with assistance of carrier protein
- Carrier protein aid movement of polar molecules
- Movement down concentration gradient
- Energy comes from concentration gradient
- Passive
4
Q
Active Transport
A
- Move molecules against concentration gradient
- Substance binds to carrier proteins that change conformation to move substance across membrane
- Active(requires energy from ATP)
5
Q
Secondary Active Transport
A
- Carried against concetration gradient without ATP catabolism
- Kinetic energy of movement of one substance down gradient powers transport of another substance against gradient
- Do not require ATP
- Sequential binding induces conformational change
6
Q
Channels
A
- Membrane spanning protein forms pore through membrane
- 4-5 protein subunits
- Pore loops dangle inside channel
- Physical properties of pore loops create a selectivity filter
7
Q
Gated channels
A
- Membrane channels are not kept open
- Channels close off by branch of protein called “gate”
- Under certain conditions, gate close and no diffusion takes place
8
Q
Ligand Gated Channels
A
-Binding of receptor with ligand trigger events at membrane, such as enzyme activation
9
Q
Voltage Gated Channels
A
- Some channels are sensitive to potential difference across membrane(depolarization), changes conformation
- Voltage sensing mechanism is in 4th transmembrane domain(S4 segment -> positively charged)
- S4 sticks out to side like a wing(natural position is up, down=shut)
- When polarized, positively charged wing is attracted downwards to negatively charged inner membrane surface(close channel)
- Depolarization to -50 mV no longer provides electrical attraction, so wing migrates back up(open channel)
10
Q
Endocytosis
A
- Inward pinching of membrane to create a vesicle(outside to inside)
11
Q
Exocytosis
A
- Partial/Complete fusion of vesicles with cell membrane for bulk transport of molecules(inside to outside)
- Kiss and Run: Secretory vesicles dock and fuse at plasma membrane at fusion pores, and can connect/disconnect several times before contents are emptied. Generally used for low rate of signaling
- Full Exocytosis: Complete fusion of vescile with membrane, leading to total release of vesicle contents and necessary for delivery of membrane proteins and high levels of signaling. Must be counterbalanced with endocytosis to stabilize membrane surface area
12
Q
Membrane Potential
A
- To generate MP
- Create concentration gradient with enzyme ion pump must actively transport certain ion across membrane
- Semi-permeable membrane: allows one ion to diffuse across membrane more than others
- Diffusion of ion species down gradient creates an electrical gradient
13
Q
Na+/K+ Pump
A
- All cell membrane is loaded with Na+/K+ pump
- Na+/K+ dependent ATPase is enzyme that moves Na+ out of cell and K+ into cell by breaking down ATP
- For each ATP broken down, 3 Na+ out and 2 K+ in
- Na/K inequality causes potential difference of -10 mV
14
Q
Resting Membrane Potential
A
- Resting membrane potential is -70 mV
- due to diffusion of K+ ions outwards
- Resting membrane most permeable to K+ ion(K+ leakage channels open)
- Cations accumulate on outside of membrane, leaving net negativity inside membrane
- Efflux occurs until further diffusion of K+ is repelled by electromagnetic force(equilibrium situation)
15
Q
Equilibrium Potential
A
- At equilibrium, electrical work to repel outward cation diffusion equals chemical work of diffusion down gradient
- Calculated using Nernst equation(describes balance of chemical work of diffusion with electrical work of repulsion)
- K+ equilibrium potential is -90 mV(not resting potential)
- Na+ and Cl- ions also diffuse and play a role
- Actual membrane potential can be calculated using Goldman equation
16
Q
Na+ Equilibrium Potential
A
- If membrane properties change to make membrane more permeable to Na+, more Na+ inwards and more positive inside
- ENa+ = -60 mV
17
Q
Cl- Ions
A
- Cl- ions pushed out of cell
- Cl- ions more concentrated on outside in the extracellular space
- Due to anion proteins present on inside
18
Q
Action Potential(AP)
A
- Short-lived impulse signal due to change in MP
- Can only produce an AP in membrane that contains voltage-gated Na+ channels
- Na+ channel makes membrane excitable
- When Na+ inactivated, K+ leakages is main current and resting potential restored
19
Q
Generation of Action Potential
A
- Resting membrane potential(-70 mV)
- Depolarizing stimulus(- 50 mV)
- Membrane depolarizes and Na+ channels and K+ channels begin to open
- Rapid Na+ entry depolarizes cell(more positive)
- At peak, Na+ channels close and slower K+ channels open
- K+ moves from inside to outside
- K+ channels remain open and hyperpolarizes cell
- K+ channel closes and less K+ leaks out of cell
- Cell returns to resting membrane potential
20
Q
Threshold
A
- Minimum depolarization necesssary to induce regenerative mechanism for opening of Na+ channels
- Subthreshold stimulus: stimulus that causes depolarization that is less than -50 mV(opens some Na+ channels but not enough to for AP)
- Suprathreshold stimulus: More than enough depolarization
21
Q
All or None Principle
A
- Action potential from threshold and suprathreshold have same magnitude(AP fires or doesn’t fire)
22
Q
Refractory Period
A
- After generation of AP, there is period in which all or some Na+ channels are inactivated
- Na+ channels remain inactivated until membrane potential drops below threshold, then channels reconfigure and cell becomes excitable again
- Absolute RP: No channels reconfigured
- Relative RP: some but not all channels are reconfigured
23
Q
Depolarization Block
A
- Keep membrane depolarized(keep at 20 mV above threshold) -> Na+ channels become permanently inactivated and cannot generate AP
- Destroy concentration gradient for K+ by introducing more K+ into extracellular space(result in permanent Na+ channel inactivation)
24
Q
After-Hyperpolarization
A
- Due to the presence of extra K+ channels(in conjunction with K+ leakage channels), created outward K+ current
- Results in MP to be more polarized
- Voltage gated K+ channels cause hyperpolarization after AP
- MP might be repolarized to -80 mV
25
Impulse Conduction
- When a patch of excitable membrane generates an AP, causes influx of Na+ and reverse potential difference across membrane
- Temporarily goes from "-" on inside to "+"
- Source of depolarizing current for adjacent membrane(Na+ channels open)
- AP propogates from origin across the rest of cell until reaching axon terminal
26
Excitable Cells
- Most cells are not excitable(don't generate AP and don't have volatage gated Na+ channels)
- Conduct passive currents but don't generate AP, most cells don't carry signals across any distance(don't have axon)
- Axon is long extension of cell body that carries AP to some other location
- Only neurons with long axons and muscle cells generate propagating APs
- Losing signal as current travels across membrane
26
Length Constant
- Length constant defined with internal resistance, extracellular fluid resistance, and membrane resistance
- Ri: internal resistance
- Rm: membrane resistance
- sqrt(Rm/Ri)
27
Cable properties
- λ measures how quickly potential difference disappears as a function of distance
- Conduction velocity of AP depends on λ
- λ increases by increasing diameter(larger diameter, less internal resistance -> less voltage lost)
- Higher membrane resistance -> less current leaked out
28
Myelination
- Increasing membrance resistance(myelination) most efficient way of increasing conduction velocity
- Glial cells assist nervous system and required for nutrition and increased membrane resistance
- Specialized glial cells wrap around successive section of axon > myelin sheath
- 50-100 layers wrapping around axon -> increases membrane resistance -> reduces leakage out of membrane
- Schwann cells wraps around a single portion of axon. Oligodentrocytes wraps a bunch of axons individually
- Small gaps left between adjacent portions of myelin sheath -> Node of Ranvier
29
Axon terminal
- AP will be conducted along membrane right to end of cell
- AP cannot turn around or re-propogate(one-way)
29
Saltatory Conduction
- If there is AP on one node, depolarizing current is strong enough and will travel down axon for many nodes
- Sufficient strength to bring all following nodes to threshold potential
- AP at one node will bring next 5-10 nodes to -55 mV to generate APs on all next nodes
- Myelin prevents leakage of current across nodes
30
Unmyelinated Axons
- Unmyelinated axons do not have extensive wrapping around outside
- Slow conduction velocity
- Both Na+ and K+ channels are intermixedd
- Majority of axons are unmyelinated
- Schwann cell and oligodendrocyte engulf unmyelinated axons to provide insulation(Remak bundle)
31
Electrical Synapse
- At electronic synapses, adjacent membranes are about 35A apart
- Gap junction bridged by connexions to allow small ions to cross
32
Chemical Synapses
- Synapse is defined by presynaptic surface(bouton contains vesicles) and postsynaptic membrane(membrane of adjacent neuron)
33
Axon Terminal
- Axons end in boutons filled with vesicles
- Vesciles contain neurotransmitters which is released into extraceullar fluid
34
Vesicle Release
- Trigger for exocytosis is Ca++ ions
- Bouton membrane contains voltage gated Ca++ channels which open when depolarized by AP currents
- AP depolarizes bouton membrane, reaches threshold for opening Ca++ channels(-50 mV)
- Ca++ diffuses into bouton, triggers cascade of reactions to result in vesicle exocytosis(kiss & run or full fusion
35
Post-Synaptic Receptors
- Transmitter agent diffuses across synapse and binds to specific site on receptor protein embedded in postsynaptic membrane
- Binding of transmitter causes change in shape of receptor protein
- Ionotropic: opens channels
- Metabotropic: initiates a metabolistic cascade to activate enzymes
- Receptor determines effect not transmitter
36
Ionotropic Effects
- Ligand binding opens an ion channel
- Binding of transmitter results in post-synaptic membrane potential(PSP)
- Duration of PSP about 20-40 ms
- EPSP(excitatory, depolarizing): Na+ and K+
- IPSP(inhibitory, hyperpolarizing): Cl- or K+
37
Ligands for Ionotropic Receptors
- Acetylcholine
- Glutamate
- GABA
- Glycine
38
Metabotropic Effects
- Binding of ligand activates G-protein coupled enzyme
- Enzyme result in increase production or destruction of secondary messengers
- 2nd messengers either cAMP, cGMP, or InP3
- 2nd messengers activates other enzymes(eg. phosphokinases)
- Phosphorylation of membrane proteins result in modulation of ion channels
- Ionotropic more immediate(opens ion channels directly)
- Metabotropic receptor takes time
- Not necessary there is any change in MP
- Change is slow because it has to go through all enzyme activity first before influencing ion channels
39
β-Adrenoreceptor
- β-receptor is a metabolic receptor for noradrenalin
- Binding of NA to receptor activates adenyl cyclase via G-protein
- adenyl cyclase increase cAMP production
- cMP activates kinases to phosphorylate membrane Ca++ channel
- increase in Ca++(increases contractility in heart muscle)
- Beta blockers decrease Ca++ availability and decrease contractility
40
Ligands for Metabotropic receptors
- ACh: Muscarinic receptor
- Peptides: substance P, β- endorphin, ADH
- Catecholamines: noradrenaline, dopamine
- Serotonin: adenosine, ATP
- Gases: NO, CO
41
Spread of PSPs
- PSPs generated in inexcitable membrane: neuronal dendrites and cell bodies(low density of voltage-gated Na+ channels)
- Cannot generate an AP
- Nearest excitable membrane is beginning of axon -> trigger zone
-Binding of transmitter generates PSP
- Spread through passive conduction across membrane to get to initial segment of axon
42
PSP Summations
- Loss of current as you go along membrane before reaching trigger zone
- Spatial Summation: Large number of EPSPs in synchrony
- Temporal Summation: EPSPs last for 30-40ms in duration before dying out, successive inputs on any synapse generates subsequent EPSPs that add on to pre-existing EPSPs
43
Inhibitory Post-Synaptic Potential
- IPSPs tend to located on cell soma, interposed 1/2 way between where EPSP is generated and trigger zone
- Can shunt depolarizing EPSP currents out of cell(stop EPSP from reaching trigger zone)
- IPSPs are more important than EPSPs, more specific than EPSPs
44
IPSP(Cl- Channel)
- IPSP involves opening of Cl- channel
- ECl- is close to resting MP
- Depolarizing membrane and opening Cl- channels bring MP back down to -70 mV
- net effect of Cl- clamps the MP to prevent excitation
45
Spike Train
- Depolarizing trigger zone to threshold and sustain depolarization for long time(500 ms) generates continious stream of AP > Spike Train
- After each spike, hyperpolarize membrane to restore Na+ channels
- Need hyperpolarization to generate another AP
- Idea is to overcome depolarization block
- After hyperpolarization fades away, MP shoots back up where EPSP takes it and generate new spike until EPSP fades away
46
Receptor Potential
- Change in MP due to receipt of signal from exterior sensory cue
- Energy from the environment reacts with membrane proteins and causes depolarization
- Similar to PSP
47
Olfactory Receptor
- Specific receptor proteins bind specific odarant
- Activates cAMP GPCR -> cAMP binds to ion channels and allow cations(Na+ and Ca++) to go through -> depolarize membrane
- Depolarizing current travels down membrane to trigger zone of axon
48
Transmission of Vesicle
- Depolarizing current don't produce AP, travel through membrane and depoalrize membrane sufficiently, influx of Ca++ ions trigger exocytosis vesicles, sensory cell releases vesicles and doesn't produce AP
- Release neurotransmitters by opening Ca++ without AP production
- Taste Receptor
49
Adaptation
- MP can decay over time
- Original voltage not sustained even though stimulus may be constant
- Slowly Adapting: Receptor potential sustained for duration of stimulus, interested in overall magnitude of stimulus
- Rapidly Adapting: Receptor potential elicited by change in stimulus energy, decay to zero when stimulus is constant, interested in how quickly stimulus is being delivered, velocity of stimulus being delivered
50
Habituation
- Habituation is response to successie stimuli in time
- Repeated identical stimuli in succession elicit progressively weaker responses
- Depends on cell
51
Coding of Stimulus Intensity
- Receptor potential will vary directly in proportion with intensity of stimulus
- Greater stimulus intensity -> greater receptor depolarization -> more transmitter released and/or higher AP frequency
- Greater depolarization -> faster membrane will be brought up from hyperpolarization to generate a spike
- Impulse frequency will always be limited by refractory period
- As stimulus intensity increases, recruit higher threshold sensory neurons
52
Receptive Field
- Each sensory neuron responds to a particular spatial area
- Receptive field of a given sensory neuron is territory in which you could activate the neuron
53
Blood-Brain Barrier
- Brain and spinal cord are protected from general circulation and the body
- Ionic composition of extracellular fluid around neuron must be carefully controlled
- Can not change excitability of membrane, can not have neurotransmitters floating around randomly
- Extracellular fluid in neuronal environment are carefully regulated through Blood-Brain Barrier
- 2 Fold Entity: Between blood vessels and interstitial fluid and blood vessels and CSF
- eg. Parkinson's Disease: L-dopa crosses BBB and converted to dopamine
54
Areas Lacking the BBB
- Most of the brain protected by BBB, but not continuous
- At some places, it is essential for neurons to communicate freely with blood stream(hypothalamus)
- Pituitary glands directly connected to hypothalamus -> BBB broken to allow release of hormones
- Circumventricular organs(around 3rd ventricle), BBB is broken so neurons can sense specific chemical
- BBB broken in areas that interact with endocrine system or requires sensitivity to metabolites in plasma
55
Brain Encasings
- Skull
- Meninges:
- Dura Mater: tough membrane sac containing brain and spinal cord
- Arachnoid membrane: More delicate tissue
- Pia mater: Lies right on top of brain, tethered to Arachnoid by Arachnoid "Trabeculae"
- Between arachnoid membrane and Pia matter -> Subarachnoid space(filled with CSF) -> brain floats to protect from mechanical stress
- Reticular Formation: Collection of loose nerve cells that connect brain and behaviour
- In subarachnoid space -> BBB in between capillaries and brain tissue
55
Ventricles
- Cavities deep inside the brain
- Large curving lateral ventricle inside each cerebral hemisphere(paired structure along the midline)
- LV empties into 3rd ventricle, in the middle, deep under the cerebral hemisphere
- 3rd ventricle communicates via "Aqueduct of Sylvius" to 4th ventricle
- From 4th ventricle, "central canal" goes in the middle of spinal cord
- All ventricles filled with CSF
- CSF produced in ventricle drains through ventricle of central canal -> CSF moves through other parts of the brain and exits at top of the brain into large venous sinus
- 1/2 CSF drains through Arachnoid Villi into venous system
56
Arachnoid Villi
- Out pouching of the arachnoid tissue, sticks out through the dura mater into venous sinus
57
Choroid Plexus
- Produces most of CSF
- Made of epithelial cells connected by tight junctions
- Produces CSF continuously(550 mL/day) as cleansing mechanism
- Dense network of capillaries ballooning out into ventricular wall with tight junction (everything has to be transported)
58
Cerebrospinal Fluid(CSF)
- Fills ventricles and subarachnoid space
- Same osmolarity and Na+ as blood
- Reduced K+, Ca++, and Mg++
- Total volume on average person is 215 mL
- Cranial CSF is 140 mL and spinal CSF is 75 mL
- Serves as cushion in subarachnoid space
- Lumbar puncture: technique to collect CSF for analysis
59
Astrocytes
- Walls of capillaries are plastered with end feet of glial cells, particulary astrocytes
- Provide bridge between neurons and blood vessels
- Efficient at glycolysis
- Produce lactate as end product(used for ATP production)
- Remove neurotransmitters and provide energy substances for neurons
60
Local Blood Flow
- Astrocytes signal BV when to dilate or constrict
- Have connections with neuron at synapse, and when detection of increased signaling, send metabolic signal to BV, signaling neuronal activity level
- Glutamate in synapses trigger Ca++ release within astrocytes, Ca++ travels through astrocytes and triggers prostaglandin(PGE2) release at end foot -> PGE2 causes vasodilation(increase blood flow)
PSL 300
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