NEURO&MIDTERM&STUDY&GUIDE&

Brain&Cells&

Neurons(

•! Transmit&information&either&by&electrical&or&by&chemical&signaling&via&synapses&(junction&between&one&neuron&and&the&next)&

•! Structure&of&neuron&limits&its&ability&to&conduct&electric&signal&

•! Have&poor&conducting&properties&

•! Soma:&cell&body&

•! Dendrites:&filaments&that&emanate&from&cell&body;&bring&information&to&the&cell&body&

•! Axon:&starts&at&the&cell&body&at&a&site&called&the&axon(hillock&and&travels&to&the&site&in&the&nervous&system&where&it&connects&with&another&nerve&cell&or&different&type&of&cell;&takes&

information&away&from&cell&body&

&

&

&

&

((((((((((((((

Neuronal&Connections&

●! Divergence:&neurons&branching,&typical&for&sensory&system&

●! Convergence:&progressively&converging&connections,&typical&for&motor&neurons&

●! Lateral&connections:&sideways&

●! Recurrent&connections:&feedback&

(Neuroglial(Cells((

•! Protect&and&support&neurons,&its&development&and&function&

•! Produce&myelin&sheaths&to&wrap&(insulate)&nerve&fibers,&and&thus&to&direct&and&maintain&

action&potential&propagation&(to&direct&trains&of&action&potential&toward&one&side&of&the&

cell).&

•! Glial&cell&plasma&membranes&express&variety&of&ion&channels&(Na+/K+/Ca2+),&as&well&as&

receptors,&pumps&and&transporters:&

o! VoltageXactivated&K+&and&Ca2+&channels&

o! Ligand&gated&Na+&and&Ca2+&channels&

o! Resting&K+&channels&

o! Chloride&channels&

o! Ion&pumps&(H+,&HCO3X)&

o! Transporters&(Glu;&Gly;&GABA)&

o! Receptors&(for&most&neurotransmitters)&

•! Activation&of&Na&and&Ca&channels&does&not&trigger&action&potential&

•! Like&neurons,&they&are&activated&(excited)&by&neurotransmitters&

•! How&do&glial&cells&differentiate&from&neurons?&

o! Glial&cells&have&resting&potentials&greater&(more&negative&inside)&than&neurons&

o! Glial&cells&do&not&conduct&action&potentials&&&

&

Types&of&Glial&Cells&in&the&Nervous&System:&

CNS:&

•! Oligodendrocytes((supportive)&!&produce&myelin&to&insulate&large&axons&in&the&CNS.&Its&

counterparts&in&PNS&are&Schwann(cells,&which&surround&peripheral&axons&(nerves).&•! Microglia&(protective)&!&remove&cell&debris&and&fight&pathogens&in&the&brain,&and&are&

involved&in&inflammatory&response&of&the&CNS&(reprints&brain’s&main&immune&response).&

•! Astrocytes&(communication&and&processing)&!&most&abundant&cell&in&the&brain;&they&

support&and&communicate&with&neurons&

o! They&release&neurotransmitters&in&CaXdependent&manner,&analogous&to&

transmitter&release&process&in&neurons.&&

o! They&respond&to&electric&and&chemical&stimuli,&propagating&electric&signals&

through&the&astrocytes&network&via&gap&junctions,&but&do&not&establish&gap&

junctions&with&neurons.&

o! Communicate&with&neurons&by&releasing&glutamate&and&other&transmitters&

•! Radial(glia&(development)&!&regulate&development&and&regeneration&of&CNS&and&PNS&

(together&with&Schwann&cells).&

&

Glial&cell&membrane&

•! Potassium&conductances&predominate&

•! Ions&other&than&potassium&make&only&a&small&contribution&to&the&resting&membrane&

potential&

o! Reducing&the&potassium&concentration&from&the&normal&3.0mM&to&0.3mM&!&

hyperpolarizes&the&membrane&

o! Increasing&the&potassium&concentration&to&30mM&!&depolarizes&by&59mV&

•! The&relation&between&potassium&concentration&and&membrane&potential&predicted&by&

the&Nernst&equation&accurately&fits&the&experimental&results,&except&at&very&low&

extracellular&potassium&concentrations.&

•! Neurons&are&less&sensitive&than&glia&to&small&changes&in&potassium&concentration&&

&

Classes&of&Electrical&Signals&

Local(Graded(Potentials&●! Generated&by&extrinsic&stimuli&(light,&sound&or&touch)&

●! Signals&are&graded&

●! Localize&to&the&site&of&origin&

●! Their&spread&depends&on&the&passive&properties&of&the&nerve&cell&

●! Resting&potential&reduces&(depolarization)&

●! As&it&spreads,&it&becomes&smaller&in&amplitude&

●! If&cell&is&small,&then&it&reaches&other&end&to&release&chemical&transmitter&&

●! It&is&a&passively&conducted&electrical&signal&

&

Action(Potentials&●! Generated&by&LGP&

●! Propagate&rapidly&over&long&distances&

●! Fixed&in&amplitude&(0.1V)&and&duration&(1ms)&that&rapidly&propagates&along&nerve&fibers&

(120m/s)&without&dissipation&

●! It&is&a&triggered,&explosive,&allXorXnothing&event&

●! It&is&is&initiated&by&signals&provided&they&reach&critical&level&(threshold)&

●! At&its&peak,&inside&is&positive&compared&to&outside&

●! Must&be&completed&before&another&can&start&

●! After&each&action&potential,&there&is&a&refractory&period&

●! Starts&passive&along&axon&(LGP),&but&it&falls&off&steeply&with&distance&but&it&exceeds&

threshold,&making&action&potential&provide&an&electrical&stimulus&to&the&next&region&of&

the&axon&to&be&invaded&

●! Intensity(of(stimulus(is(coded(by:(○! Frequency&of&firing&→&greater&depolarization,&higher&frequency&of&firing&

○! Number&of&neurons&being&activated&

Ion&Channels&

●! Nerve&cells&at&rest&have&steady&membrane&potentials&X30mV&to&X100mV&(negative&signs&

means&that&inside&of&membrane&is&negative&compared&to&outside)&

●! Signaling&is&mediated&by&changes&in&membrane&potential&

●! Appropriate&stimulus&can&cause:&

○! Depolarization((making&membrane&potential&less&negative)(○! Hyperpolarization((making&membrane&potential&more&negative)(

●! Cell&membrane&

○! Composed&mainly&of&lipids&and&proteins&

○! Lipid&molecules&arranged&in&bilayer&with&polar,&hydrophilic&heads&facing&outward&

and&hydrophobic&nonpolar&tails&extending&to&the&middle&of&the&layer&

○! Lipid&permeable&to&water&but&impermeable&to&ions&

○! Embedded&in&lipid&bilayer&are&protein&molecules&that&form&ion&channels&

○! Other&proteins&function&as&transport&molecules&(pumps&and&transporters)&that&

move&substances&across&membrane&against&their&electrochemical&gradients&

●! Single&Channel&!&transmembrane&protein&spanning&extracellular&and&intracellular&

spaces&

●! Ions&move&through&channels&passively,&driven&by&electrochemical&gradient(●! Chemical(gradient(–&concentration&difference(●! Electrical(gradient&–&electrical&potential&difference&(mV)(●! The&direction&and&equilibrium&for&ion&flux&through&channels&are&determined&by&the&

electrostatic&and&diffusion&driving&forces&across&the&membrane&

●! Each&channel&has&its&own&characteristic&mean(open(time&around&which&durations&of&openings&fluctuate&

●! During&resting&potential&=&K+&and&ClX&channels&are&open&

●! Factors&that&regulate&current&flow&through&ion&channels:&

○! They&can&be&activated((freq.&of&opening&increases)&or&deactivated((freq.&of&opening&decreases)&by&a&stimulus.&Probability&of&channel&to&open&does&not&mean&

an&increase/decrease&in&mean&open&time.&

○! Conformational&state&in&which&activation&no&longer&occurs&

�! In&channels&that&respond&to&depolarization&(voltage&activated)&&=&

inactivation&�! In&channels&that&respond&to&chemical&stimuli&(ligand&activated)&=&

desensitization&○! Open&channel&block&X&molecule&or&other&ions&bind&and&block&channel&

&

&

&

Channel(Activation((classifications&not&ultimately&exclusive)&

1.! Channels&activated&by&physical&changes&in&the&cell&membrane&(mechanic&vs.&voltage&

sensing)&

a.! VoltageJactivated&!&changes&in&membrane&potential&

b.! StretchJactivated&!&respond&to&mechanical&distortion&of&the&cell&membrane&

2.! LigandJactivated(channels&(chemical&sensing)&

a.! Extracellular&activation&!&neurotransmitters&

b.! Intracellular&activation&!&sensitive&to&local&changes&in&the&concentration&of&

specific&ions&

&

Measurement(of(Channel(Electric(Activities((-! Patch&Clamp&&

o! Tip&of&a&small&glass&pipette&is&sealed&to&the&membrane&of&a&cell&

o! When&pipette&is&connected&to&appropriate&amplifier,&small&currents&cross&the&

patch&of&membrane&inside&the&pipette&tip&can&be&recorded&

o! The&recorded&events&consist&of&rectangular&pulses&of&current,&reflecting&the&

opening&and&closing&of&single&channels&

o! In&graph&of&patch&clamp&recordings:&

"! Downward&deflections&indicate&current&flowing&into&the&cell&=&inward&

current&

"! Upward&deflections&=&outward&current&

-! Intracellular&recording&with&microelectrodes&

o! A&sharp&glass&micropipette,&filled&with&a&concentrated&salt&solution,&serves&as&an&

electrode&and&is&connected&to&an&amplifier&to&record&the&potential&with&its&tip&

&

Channel(Conductance((XChannel&current:&direct&measure&of&how&rapidly&ions&move&through&a&channel&

XCurrent&depends&on&channel&properties&and&on&transmembrane&potential&

&

Effect&of&Potential&on&Currents&

Using&patch&clamp&recording&system:&

XWhen&a&potential&of&+20mV&is&applied,&each&channel&opening&results&in&a&pulse&of&outward&

current&because&positively&charged&potassium&ions&are&driven&outward&through&the&channel&by&

the&electrical&gradient&between&the&pipette&solution&and&the&bath&

XWhen&inside&is&made&negative&by&20mV,&current&flows&the&other&way,&through&the&open&

channel&into&the&pipette&

XThe&relationship&is&linear:&

& I&=&γV&(Ohm’s&law)&

I&=&current&

γ&=&channel&conductance&V&=&voltage&

*Current&directly&proportional&to&the&voltage&applied&to&it&

XIon&current&flow&through&the&single&channel&(conductance)&depends&on:&

-! Channel&permeability&(ease&with&which&ions&can&pass&through&the&open&channel)&

-! Ion&concentration&gradient&

(Equilibrium(Potential((

•! Is&the&electric&potential&at&which&net&flux&of&given&ion&across&the&membrane&is&0;&depends&

only&on&the&ion&concentration&on&either&side&of&the&membrane&–&not&on&the&properties&of&

the&channel&&

•! Described&by&the&Nernst(Equation&o! Calculates&the&exact&value&of&the&equilibrium&potential&for&each&ion&in&mV&

o! Takes&into&consideration:&

"! Charge&of&ion&

"! Temperature&

"! Ratio&of&the&external&and&internal&ion&concentrations&

(EK&=&58&log&(&[K]0&/&[K]i&)&

[K]0&=&outside&concentration&

[K]i&=&inside&concentration&

(*Approximate&Equilibrium&Potentials*&

X&Resting&Membrane&Potential&=&X70mV&&

X&Sodium&=&+50mV&

X&Potassium&&&chloride&=&X90mV&

X&Calcium&=&+120mV&

(Structure&of&Ion&Channels&

LigandJActivated(Channels(!(Nicotinic(Acetylcholine(Channel((nACH(or(ACh)(•! 5&subunits&(pentamer)&that&form&a&circular&array&around&a&central&pore&

o! 2α&subunits&–&contain&the&receptor&sites&for&ACh&(ligand)&•! Has&transmembrane,&extracellular&and&intracellular&domains&

•! Each&subunit&contains&4&membraneXspanning&regions&(M1,&M2,&M3,&M4)&connected&by&

intra&and&extracellular&loops.&

(((((((((((

•! Structure&based&on:&

o! Receptor&cloning&(primary&structure;&higher&structures:&XXray;&NMR;&EM)&

o! SiteXdirected&mutagenesis&studies&

(Anion/Cation&Channel&Selectivity((

•! Ion&selectivity&is&based&on&aa&composition&of&extracellular&and/or&membrane&spanning&

domains&(and&structure&of&the&channel).&

•! Structural&similarity&among&channels&is&based&on&their&relative&high&degree&of&sequence&

homology&

•! In&cationXselective&channels&!&the&loops&lining&the&walls&of&the&projecting&channel&

vestibules&have&a&net&excess&of&negative&charges&

•! In&anionXselective&channels&!&excess&is&of&positive&charges&

•! GABA&Receptor:&ClX&

•! Glycine&Receptor:&ClX&

•! Ach&Receptor:&Na+&

•! 5XHT&Receptor:&Na+&

(VoltageJGated(Channels(

A.! Sodium(channel(a.! Responsible&for&the&

depolarizing&phase&of&the&

nerve&action&potential&

b.! Has&4&domains,&each&

domain&is&architecturally&

equivalent&to&one&subunit&of&

AChR.&&

c.! Each&domain&has&6&

transmembrane&regions&

d.! PoreXforming&structure&between&S5XS6&

B.! Calcium(channel(a.! In&some&tissues,&responsible&

for&action&potential&

generation&or&prolongation&

and&subserve&many&other&

functions&such&as&muscle&

contraction,&release&of&&

neurotransmitters&

b.! Structure&similar&to&sodium&

channels&→&poreXforming&

structure&between&S5XS6&

C.! Potassium(channel(a.! Associated&with&membrane&repolarization&

b.! Amino&acid&sequence&much&shorter&

c.! Resembles&a&single&domain&of&the&sodium&channel&

d.! Complete&channel&is&formed&by&an&assembly&of&4&

subunits&

e.! Selectivity&for&potassium&is&achieved&by&both&size&and&

the&molecular&composition&of&the&selectivity&filter&

(Other(Channels(

•! Common&tetra&structural&motive:&

o! Tetramer&(4&subunits)&

o! 4&domains&

•! Subunits&or&proteins&are&organized&in&circular&pattern&in&the&membrane&to&form&a&

channel&

•! Channels&differ&not&only&by&aa&composition&of&their&membrane&spanning&domains&but&

also&by&the&number&of&membrane&spanning&regions:2X11.&&

&

Transport&Across&Cell&Membranes&

•! All&ion&movements&through&channels&are&passive,&driven&by&the&concentration&and&electrical&gradients&across&the&cell&membrane.&

•! Ions&that&leak&into&or&out&of&the&cell&at&rest&or&during&electrical&activity&are&recovered&by&

active(transport&mechanisms&that&move&ions&back&across&the&membrane&against&their&

electrochemical&gradients.&

•! Primary(Active(Transport&o! Use&energy&provided&by&hydrolysis&of&ATP&

o! SodiumXpotassium&exchange&(3Na&out/2K&in)&!&Na/KXATPase&[electrogenic]&

o! Ca2+XATPase&

•! Secondary(Active(Transport(&o! Uses&energy&provided&by&the&flux&of&an&ion&(usually&sodium)&down&its&established&

electrochemical&gradient&to&transport&other&ions&across&the&cell&membrane,&

either&in&the&same&direction&(cotransport)&or&in&the&opposite&direction&(ion(exchange).&

o! Na/Ca&exchanger&

o! Cl/Na&

&

&

&

SodiumJPotassium(Exchange&!&electrochemical&gradient&drives&Na+&into&the&cell,&while&driving&

K+&out&of&the&cell&(3Na&out/2K&in)&

•! InwardXfacing&binding&sites&have&a&high&affinity&for&sodium&and&a&low&affinity&for&

potassium&

•! Previously&bound&potassium&ions&are&released&and&three&sodium&ions&are&bound&

•! Sodium&binding&is&followed&by&ATP&binding&and&phosphorylation&of&the&enzyme&

•! The&phosphorylated&enzyme&undergoes&a&conformational&change&such&that&its&binding&

sites&face&the&extracellular&solution&

•! OutwardXfacing&sites&have&a&low&affinity&for&sodium&and&a&high&affinity&for&potassium,&

and&they&bind&two&potassium&ions&

•! Potassium&binding&leads&to&desphosphorylation.&Dephosphorylation&is&followed&by&a&

return&to&the&following&conformation&

&

Calcium(Transport((Primary&Transport&

(Ca2+&Pumps)&

XCaATPase&

XTransport&cycle&analogous&to&sodiumXpotassium&ATPase&

XBegins&with&attachment&of&two&Ca2+&to&high&affinity&sites&facing&cytoplasm&

&

Secondary&Transport&&

Ca2+&Transporters&!&NaXCa&exchanger&(electrogenic)&[NCX]&

XTransport&molecule&carries&one&calcium&outward&for&each&group&of&three&sodium&ions&entering&

the&cell&

XCalled&into&play&in&excitable&cells&when&calcium&influx&due&to&electrical&activity&overwhelms&the&

transport&ability&of&the&ATPase&

XForward&cycle:&facilitated&by&hyperpolarization&

XReversed&cycle:&facilitated&by&depolarization&

&

Cotransport&!&K+/Cl

X&(electroneutral)&

XSince&ion&transport&by&the&system&is&insensitive&to&extracellular&sodium&concentration,&it&

appears&likely&that&energy&required&for&outward&chloride&transport&is&supplied&solely&by&the&

outward&movement&of&potassium&down&its&electrochemical&gradient&

&

&

&

&

Transport(of(Neurotransmitters((Uptake&by&Synaptic&Vesicles&

XCoupled&to&H+Xgradient&&

XHydrogen&ATPase&transports&protons&into&the&vesicle&from&the&cytoplasm,&creating&an&

electrochemical&gradient&for&proton&efflux&

XProton&efflux&through&the&secondary&transport&molecule&provides&the&energy&for&accumulation&

of&the&neurotransmitter&in&the&vesicle&

&

Uptake&by&Cell&

XServes&two&purposes:&(1)&Transmitter&is&removed&from&extracellular&space&in&the&region&of&the&

synapse;&this&removal&helps&terminate&its&synaptic&action&and&prevents&its&diffusion&to&other&

synaptic&regions.&(2)&Transmitter&molecules&recovered&by&the&nerve&terminal&can&be&packaged&

again&for&reXrelease.&

XAll&uptake&mechanisms&use&the&electrochemical&gradient&for&sodium&to&carry&transmitter&

substances&across&the&plasma&membrane&into&the&cytoplasm&

XTwo&major&categories&of&transmitter&uptake&systems:&

& (1)&Sodium&influx&and&potassium&efflux&are&coupled&to&uptake&process&

& Ex:&Glutamate&uptake&is&coupled&to&the&influx&of&two&sodium&ions&and&efflux&of&one&&&&

&&&&&&&&&&&&&potassium&ion,&and&it&is&accompanied&by&the&extrusion&of&one&OHX&(or&one&HCO3

X)&ion&&

& (2)&Couples&sodium&influx&and&influx&of&chloride&

& Ex:&Transports&GABA,&glycine,&norepinephrine,&dopamine,&serotonin.&In&each&cell&cycle&&

&&&&&&&&&&&&&one&or&two&sodium&ions&enter&the&cell,&accompanied&by&one&transmitter&molecule&and&a&&

&&&&&&&&&&&&&single&chloride&ion.&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

Generation)of)Action)Potential)•! Depolarization&increases&sodium&conductance&and,&more&slowly,&potassium&conductance&

•! The&activation&of&sodium&conductance&is&transient,&being&followed&by&inactivation&

•! The&increase&in&potassium&conductance&persists&for&as&long&as&the&depolarizing&pulse&is&

maintained&

•! Depolarization&increases&the&probability&that&sodium&and&potassium&channels&will&open.&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

First&phase&!&DEPOLARIZATION((RISING(PHASE)&XInterior&of&cell&gains&sodium&&

XThe&resulting&inrush&of&sodium&and&accumulation&of&positive&charge&on&inner&surface&of&

membrane&drives&the&potential&toward&ENa&(opening&of&a&large&number&of&voltageXactivated&

sodium&channels)&(&

Second&phase&!&REPOLARIZATION(&XAccomplished&by&a&subsequent&large&increase&in&potassium&permeability,&and&loss&of&the&

accumulated&positive&charge,&carried&now&by&the&efflux&of&potassium&ions&as&the&membrane&

returns&toward&EK&(opening&of&voltageXactivated&potassium&channels)&

XActual&amount&of&sodium&influx&is&greater&than&required&to&charge&membrane&to&the&peak&of&

action&potential&because&potassium&efflux&(carrying&charge&in&opposite&direction)&begins&before&

peak&is&reached.&

&

Effects&of&Increasing&Conductances&

&

-! Sodium&entry&reinforces&depolarization&

o! Increase&in&gNa&!&Inward&Na+&current&!&Depolarization&

-! Potassium&efflux&leads&to&repolarization&

o! Depolarization&!&Increase&in&gK&!&Outward&K+&current&!&Repolarization&

&

gNa&=&INa/&(Vm&–&ENa)&

gK&=&IK&/&(Vm&–&EK)&

g&=&conductance&

I&=&current&

Vm&=&membrane&potential&

Vm&–&E&=&driving&force&

&

Currents&during&depolarization&

-! Brief&positive&capacitative&current&(outward)&!&due&to&movement&of&potassium&and&

chloride&

-! Early&transient&phase&of&inward&current&!&due&to&sodium&entry&

-! Late&maintained&outward&current&!&due&to&potassium&movement&out&of&the&fiber&

(TTX(!&blocks&voltageXactivated&sodium&conductance&selectively;&when&poised&with&TTX,&no&

inward&current&of&sodium&is&seen,&only&outward&potassium&current&

&

TEA(!&blocks&voltageXactivated&potassium&currents&

&

Effect&of&membrane&potential&on&ion&currents&

-! Early&sodium&current&first&increases,&then&decreases&as&depolarizing&steps&increase&

(reverses&to&outward&current&at&around&the&Na&equilibrium&potential)&

-! Late&potassium&current&increases&rapidly&with&depolarization&

&

Effect&of&membrane&potential&on&ion&conductances&

-! Peak&sodium&conductance&and&steadyXstate&potassium&conductance&both&increase&with&

increasing&depolarization&

&

THRESHOLD(JThe&inward&and&outward&currents&are&exactly&equal&and&opposite,&just&as&they&are&at&rest&BUT&the&balance&of&currents&is&unstable&

&

REFRACTORY(PERIOD(XAbsolute&!&lasting&throughout&the&falling&phase&of&the&action&potential&during&which&no&

amount&of&externally&applied&depolarization&can&initiate&a&second&regenerative&response&

XRelative&!&follows&absolute;&during&which&the&threshold&gradually&returns&to&normal&as&sodium&

channels&recover&from&inactivation&and&potassium&channels&close&

(Role&of&Calcium&

XCalcium&ions&enter&the&cell&through&voltageXactivated&calcium&channels&during&action&potential&

XIn&some&neurons,&calcium&currents&become&sufficiently&large&to&contribute&significantly&to,&or&

even&be&solely&responsible&for,&the&rising&phase&of&the&action&potential&

XBecause&gCa&increases&with&depolarization,&the&process&is&a&regenerative&one,&entirely&

analogous&to&that&of&sodium&

XCalcium&ions&also&affect&excitation:&a&reduction&in&extracellular&calcium&increases&the&

excitability&of&nerve&cells&&

&

Propagation)of)Action)Potential)Current&flow&

-! The&distance&along&which&the&current&spreads&depends&on&the&conductivity&of&the&core&

and&the&effectiveness&of&the&insulation&in&preventing&current&loss.&&

-! In&an&axon,&current&is&carried&by&the&flow&of&ions&

-! The&most&abundant&small&ion&in&the&axoplasm&is&potassium,&which&therefore&carries&most&

of&the&current&

-! The&distance&the&potential&spreads&along&the&axon&depends&on&the&resistance&of&the&cell&

membrane&relative&to&that&of&the&axoplasm&

-! A&lowXresistance&membrane&with&high&ionic&conductances&allows&current&to&leak&out&

before&it&can&spread&very&far&

-! A&largerXresistance&membrane&allows&a&greater&portion&of&the&current&to&spread&laterally&

before&escaping&the&external&solution&

&

Resistance&

-! The&potential&change&produced&across&the&membrane&at&any&given&distance&is&

proportional&to&the&current&flow&across&the&membrane&at&that&point&(in&accordance&with&

Ohm’s&law)&

-! The&decrease&in&potential&with&distance&from&the&current&electrode&is&exponential,&so&the&

potential&(Vx)&at&any&distance&x&on&either&side&is&given&by:&o! Vx&=&V0eXx/λ&

-! The&peak&potential&change&(V0)&is&proportional&to&the&size&of&the&injected&current&

-! The&length(constant(of&the&fiber&(λ)&is&the&distance&over&which&the&potential&falls&to&1/e&(37%)&of&its&maximum&value.&

-! Two&parameters&(rinput&and&λ)&define&how&much&depolarization&is&produced&by&a&given&

amount&of&current,&and&how&far&that&depolarization&spreads&along&the&fiber.&

-! rm&=&membrane&resistance&|&ri&=&internal&resistance&or&longitudinal&resistance&

-! The&membrane&resistance&decreases&as&the&fiber&length&increases&because&more&

channels&are&available&for&current&to&leak&through&the&membrane&

-! The&length&constant&of&the&fiber&depends&on&both&rm&and&ri&

o! λ&=&(rm/&ri)1/2&-! Distance&over&which&the&potential&change&spreads:&

o! Increases&with&increasing&membrane&resistance&(which&prevents&loss&of&current)&

o! Decreases&with&increasing&internal&resistance&(which&resists&current&flow&along&

the&core&of&the&fiber)&

-! All&else&being&equal,&a&1cm&length&of&small&fiber&should&have&a&higher&membrane&

resistance&than&the&same&length&of&larger&fiber,&simply&because&the&smaller&fiber&has&less&

membrane&surface&area&

-! As&fiber&radius&increases,&input&resistance&decreases&

&

Propagation&

-! Action&potential&propagation&along&a&nerve&fiber&depends&on&the&passive&spread&of&

current&ahead&of&the&active&region&to&depolarize&the&next&segment&of&membrane&to&

threshold.&

-! The&distance&occupied&by&potential&depends&on&its&duration&and&conduction&velocity&

-! Near&the&leading&edge&of&the&action&potential,&where&the&membrane&potential&has&

reached&threshold,&there&is&a&rapid&influx&of&sodium&ions&along&their&electrochemical&

gradient,&depolarizing&the&cell&membrane&

-! The&inward&current&spreads&longitudinally&in&the&fiber&away&from&the&active&region&

-! Ahead&of&the&active&region&this&current&depolarizes&a&new&segment&of&membrane&toward&

threshold&

-! Behind&the&peak&of&the&action&potential&the&potassium&conductance&is&high&and&current&

flows&out&through&potassium&channels,&restoring&the&membrane&potential&toward&its&

resting&level.&

-! There&is&no&inherent&directionality&in&propagation&

-! An&action&potential,&once&initiated,&cannot&reverse&its&direction&of&propagation&this&is&

because&of&the&refractory&period&!&the&sodium&conductance&is&largely&inactivated&and&

the&potassium&conductance&is&high,&so&a&backwardXconducting&regenerative&response&

cannot&occur&

-! As&the&action&potential&leaves&the&region,&the&membrane&potential&returns&to&its&resting&

value,&sodium&channel&inactivation&is&removed,&potassium&conductance&returns&to&

normal,&and&excitability&recovers.&

&

Myelinated&Nerves&and&Saltatory&Conduction&

-! The&larger&nerve&fibers&are&myelinated&

-! Myelin&is&formed&by&Schwann&cells&and&in&the&CNS&by&

oligodendrocytes&

-! The&cells&wrap&themselves&tightly&around&axons,&and&with&

each&wrap&the&cytoplasm&between&the&membrane&pair&is&

squeezed&out&so&that&the&result&is&a&spiral&of&tightly&packed&

membranes&

-! Effective&membrane&resistance&is&increased&by&a&factor&of&

320&and&the&membrane&capacitance&is&reduced&to&the&same&

extent&

-! Myelin&sheath&is&interrupted&periodically&by&nodes&of&

Ranvier,&exposing&patches&of&axonal&membrane.&

-! The&effect&of&myelin&sheath&is&to&restrict&membrane&current&

flow&largely&to&the&node&because&ions&cannot&flow&easily&

into&or&out&of&the&highXresistance&intermodal&region&and&the&

intermodal&capacitative&currents&are&very&small&as&well.&

-! As&a&result,&excitation&jumps&from&node&to&node,&thereby&

greatly&increasing&the&conduction&velocity.&Such&pulse&

propagation&is&called&saltatory(conduction&

-! Myelinated&axons&not&only&conduct&more&rapidly&than&unmyelinated&ones,&but&also&are&

capable&of&firing&at&higher&frequencies&for&more&prolonged&periods&of&time.&

(Consequence&of&myelination&=&during&impulse&propagation,&fewer&sodium&and&

potassium&ions&enter&and&leave&the&axon&because&regenerative&activity&is&restricted&to&

the&nodes)&

-! As&myelin&thickness&increases&!&membrane&resistance&&&internal&resistance&increase&

-! Optimal:&Daxon&~&0.7&Dfiber&

-! Observed&range&in&ratio&of&axon&diameter&and&fiber&diameter&!&0.6X0.8&

&

Localization&of&Na/K&channels&in&axon&

In&myelinated&fibers:&

XvoltageXsensitive&sodium&channels&are&highly&concentrated&in&the&nodes&of&Ranvier&

XPotassium&channels&more&concentrated&under&the&paranodal&sheath&

&

Pathways&for&current&flow&between&cells&

XExtracellular&electric&signaling&(transfer&of&electric&signals&from&one&cell&to&the&adjacent&

cell)&is&mediated&by&lowXresistance&connections&“gap(junctions”.&XGap&junctions&are&made&of&connexons,&proteins&that&interact&from&apposing&cells&PM&to&form&

aqueous&channel,&and&thus&to&connect&cytoplasm&of&neighboring&cells&(conductance&is&

maintained&by&the&free&flow&of&ions&from&one&cell&to&the&next&via&gap&junctions).&

&

Recap:&The&spread&of&local&potentials&in&the&membrane,&and&AP&propagation,&along&a&nerve&

fiber,&depends&on&the&electric&properties&of&the&membrane:&composition,&density&and&

distribution&of&channels&in&the&membrane,&membrane&myelination;&membrane&diameter&(rm&and&

ri).&&

&

Direct)Synaptic)Transmission)&

Two&types&of&direct&synaptic&transmission:&

A)! Electrical(synapses&!&transmission&is&mediated&by&the&

flow&of&current&from&the&preX&to&the&postsynaptic&cell&

•! Current&flows&directly&from&one&cell&to&another&

through&connexons,&intercellular&channels&that&

cluster&to&form&gap&junctions&

•! Most&electrical&synapses&do&not&exhibit&

rectification,&but&conduct&equally&well&in&both&

directions&

•! For&cells&to&be&strongly&electrically&coupled,&the&resistance&of&the&junction&

between&the&cells&must&be&very&low&and&there&must&be&a&reasonable&match&

between&the&sizes&of&the&presynaptic&and&postsynaptic&elements&

•! Electrical&and&chemical&transmission&often&coexist&at&a&single&synapse&

&

&

•! Advantages:&

o! More&reliable&than&chemical;&less&likely&to&fail&because&of&synaptic&

depression&or&to&be&blocked&by&neurotoxins&

o! Greater&speed&

&

&

B)! Chemical(synapses&!&more&common;&a&neurotransmitter&is&released&from&the&axon&

terminal&and&binds&to&receptors&on&the&target&cell&

that&are&ion&channels&

•! Depolarization&of&the&presynaptic&nerve&

terminal&triggers&the&release&of&

neurotransmitter&molecules,&which&

interact&with&receptors&on&the&postsynaptic&

neuron,&causing&excitation&or&inhibition.&•! Complex&in&structure&

•! Synaptic(cleft&(between&terminal&and&membrane)&

•! Postjunctional(folds(!&peculiar&to&skeletal&muscle&and&not&a&general&feature&of&

chemical&synapses&

•! Motor(end(plate(!&region&of&postsynaptic&specialization&in&muscle&cells&

•! Schwann&cell&lamellae&cover&nerve&terminal&

•! Within&the&cytoplasm&of&terminal,&clusters&of&synaptic(vesicles&are&associated&with&electronXdense&material&attached&to&the&presynaptic&membrane,&forming&

active&zones&

&

&

&

&

&

&

Structure&of&Chemical&Synapse&

&

&

&

&

&

&

&

&

(((((

Synaptic(Delay(X! Only&present&in&chemical&synapses,&not&in&electrical&

X! There&is&a&pause&of&approximately&1ms&between&the&arrival&of&an&impulse&in&the&

presynaptic&terminal&and&the&appearance&of&an&electrical&potential&in&the&postsynaptic&

cell&

X! The&delay&is&due&to&the&time&taken&for&the&terminal&to&release&neurotransmitter&

X! At&electrical&synapses,&no&delay,&current&spreads&instantaneously&from&one&cell&to&

another&

&

Chemical(Synaptic(Transmission(XEntails&the&secretion&of&a&specific&chemical&by&a&nerve&terminal&and&its&interaction&with&

postsynaptic&receptors&

&

Amplitude&of&a&synaptic&potential&can&be&increased&by:&

XIncreasing&the&synaptic&conductance&(activating&more&synaptic&channels)&

XDecreasing&the&resting&conductance&

(Measurement&of&Ionic&Currents&Produced&by&ACh&

XACh&produces&a&marked,&nonspecific&increase&in&permeability&of&the&postsynaptic&membrane&to&

small&ions&

XPermeability&of&the&postsynaptic&membrane&was&increased&to&sodium,&potassium,&and&calcium,&

but&not&to&chloride&

XWith&the&muscle&membrane&potential&clamped&at&X40mV,&nerve&stimulation&produced&an&

inward&current,&which&would&have&caused&a&depolarization&if&the&fiber&had&not&been&voltageX

clamped.&

XAt&more&negative&holding&potentials,&the&end&plate&current&increased&in&amplitude.&

XWhen&the&membrane&was&polarized,&the&end&plate&current&decreased&in&amplitude.&

XWith&further&depolarization,&the&current&reversed&direction&and&was&outward.&

XThe&current&changed&from&inward&to&outward&near&zero&membrane&potential.&Accordingly,&zero&

is&called&the&reversal(potential((Vr)(!&at&this&potential,&the&inward&sodium&current&is&exactly&

equal&and&opposite&to&the&outward&potassium&current&

XChanging&the&concentration&of&sodium,&potassium,&or&calcium&in&the&bathing&solution&

resulted&in&changes&in&the&reversal&potential,&but&changes&in&extracellular&chloride&did&

not.&Conclusion&=&the&effect&of&ACh&was&to&produce&a&general&increase&in&cation&

permeability&

XThe&channel&opened&by&ACh&is&nearly&equally&permeable&to&sodium&and&potassium,&but&the&

sodium&conductance&change&is&slightly&larger&because&there&are&more&sodium&ions&than&

potassium&available&to&move&through&channels.&

&

Direct(Postsynaptic(Inhibition(Two&types&of&postsynaptic&potential(

o! Excitatory((EPSP)(!&synaptic&potential&that&excites&a&postsynaptic&cell(o! Inhibitory((IPSP)(!&inhibits&a&postsynaptic&cell(

(

XExcitation&occurs&by&opening&channels&in&the&postsynaptic&membrane&whose&reversal&potential&

is&positive&to&threshold&

XInhibition&is&achieved&by&opening&channels&whose&reversal&potential&is&negative&to&threshold.&It&

occurs&by&activating&channels&permeable&to&chloride,&an&anion&that&typically&has&the&equilibrium&

potential&at&or&near&the&resting&potential&

XAt&the&normal&resting&potential&(about&X75mV),&stimulation&of&the&inhibitory&inputs&causes&a&

slight&hyperpolarization&of&the&cell&–&the&inhibitory(postsynaptic(potential((IPSP).&XWhen&the&membrane&is&depolarized&by&passing&positive&current&into&the&cell,&the&amplitude&of&

the&IPSP&is&increased.&

XWhen&cell&hyperpolarized&to&X82mV,&the&inhibitory&potential&is&very&small&and&reversed&in&sign,&

and&at&X100mV&the&reversed&inhibitory&potential&is&increased&in&amplitude.&Reversal&potential&in&

this&experiment&is&X80mV.&

XInhibitory&channels&are&permeable&to&anions&

XGiven&that&the&inhibitory&response&involves&an&increase&in&chloride&permeability,&the&reversal&

potential&for&the&inhibitory&current&will&be&equal&to&the&chloride&equilibrium&potential&

XAt&membrane&potentials&positive&to&ECl&the&current&is&outward,&resulting&in&membrane&

hyperpolarization&(current&carried&by&influx&of&negatively&charged&chloride&ions)&

XAt&membrane&potentials&negative&to&ECl&the&inhibition&causes&an&efflux&of&chloride&ions&resulting&

in&depolarization&

&

Direct(Presynaptic(Inhibition(XResults&in&a&reduction&in&the&amount&of&transmitter&released&from&excitatory&nerve&terminals&

XFor&the&maximum&inhibitory&effect&to&occur,&the&impulse&must&arrive&in&the&inhibitory&

presynaptic&terminal&several&milliseconds&before&the&action&potential&arrives&in&the&excitatory&

terminal.&If&this&is&the&case,&it&causes&a&marked&reduction&in&the&size&of&the&excitatory&

postsynaptic&potential.&

XPresynaptic&effect,&just&as&postsynaptic&effect,&is&mediated&by&GABA&and&is&associated&with&a&

marked&increase&in&chloride&permeability&in&the&presynaptic&terminals.&

XPresynaptic(excitation(!&synaptic&inputs&that&enhance&the&release&of&transmitter&from&

presynaptic&nerve&terminals&

XThe&response&to&a&neurotransmitter&often&decreases&during&repeated&or&prolonged&application,&

a&phenomenon&called&desensitization.&&

Receptors(Mediating(Direct(&(Indirect(Chemical(Transmission((Direct&

Xmediated&by&ion&channels&in&the&postsynaptic&membrane&(ionotropic(neurotransmitter(receptors(=&ligandXactivated)&that&are&activated&by&binding&the&neurotransmitter&released&by&the&

presynaptic&cell&

&

Indirect&

Xmediated&by&metabotropic(receptors&=&postsynaptic&receptors&that&produce&an&intracellular&second&messenger.&The&second&messenger,&in&turn,&influences&the&activity&of&ion&channels,&

causing&excitation&or&inhibition&

Indirect)Synaptic)Transmission)&

&

&

&

&

&

&

&

&

At&direct&chemical&synapses&the&transmitter&binds&to&an&ionotropic&receptor.&Ionotropic&

receptors&are&ligandXactivated&ion&channels.&

&

Indirectly&acting&transmitters&bind&to&metabotropic&receptors.&Metabotropic&receptors&are&not&

themselves&ion&channels,&but&rather&activate&intracellular&second&messenger&signaling&pathways&

that&influence&the&opening&and&closing&of&ion&channels.&

&

Metabotropic(Receptors(X! G&proteinXcoupled&metabotropic&receptors&

comprise&a&superfamily&characterized&by&

seven&transmembrane&domains,&with&an&

extracellular&amino&terminus&and&an&

intracellular&carboxy&terminus.&&

X! Portions&of&the&second&and&third&cytoplasmic&

loops,&together&with&the&membraneX

proximal&region&of&the&carboxy&tail,&mediate&

binding&to&and&activation&of&the&appropriate&

G&protein.&

X! (B)&Portions&of&the&transmembrane&domains&

form&the&ligandXbinding&sites&of&metabotropic&

receptors&that&bind&amines,&nucleotides,&and&

eicosanoids.&

X! (C)&Ligands&bind&to&the&outer&portions&of&the&

transmembrane&domains&of&peptide&hormone&

receptors&

X! (D)&The&aminoXterminal&tail&forms&the&ligandX

binding&domain&of&metabotropic&receptors&for&

glutamate&and&GABA.&

&

&

&

&

&

&

G(Proteins(X! So&named&because&they&bind&guanine&nucleotides(X! Are&trimmers&made&up&of&three&subunits:&α,&β,&and&γ(X! Are&grouped&into&four&main&classes&according&to&structure&and&targets&of&their&α&

subunits:(o! Gs(o! Gi(o! Gq(o! G12(

X! A&particular&G&protein&can&couple&to&more&than&one&effector&and&different&G&proteins&can&

modulate&the&activity&of&the&same&ion&channel(((((((((((((Indirectly(coupled(transmitter(receptors(act(through(G(proteins:(

X! Activation&of&a&metabotropic&receptor&by&agonist&binding&(indicated&by&star)&promotes&

the&exchange&of&GTP&for&GDP&on&the&α&subunit&of&the&G&protein.&X! This&activates&the&α&subunit&and&the&βγ&complex,&causing&them&to&dissociate&from&the&

receptor&and&from&one&another.&

X! The&free&activated&αXGTP&subunit&and&βγ&complex&each&interact&with&target&proteins&

X! Hydrolysis&of&GTP&to&GDP&and&inorganic&phosphate&(Pi)&by&the&endogenous&GTPase&

activity&of&the&α&subunit&leads&to&association&of&the&αβγ&complex&into&the&G&protein&

complex,&terminating&the&response.&

&

Direct(G(ProteinJChannel(Interactions((Activation&of&Potassium&Channels&

X! Application&of&the&Gβγ&complex&to&the&intracellular&surface&of&an&isolated&patch&of&

membrane&from&muscle&cell&results&in&an&increase&in&potassium&channel&current&similar&

to&that&seen&when&ACh&is&added&to&the&extracellular&side&of&the&patch.&

X! Binding&of&ACh&to&muscarinic&receptors&activates&a&G&protein;&activated&βγ&complex&binds&

directly&to&and&opens&a&potassium&channel.&

&

&

Inhibition&of&Calcium&Channels&

X! Norepinephrine&released&from&sympathetic&neurons&combines&with&α2Xadrenergic&

receptors&in&the&terminal&membrane&(autoreceptors),&activating&G&protein.&&

X! The&activated&βγ&complex&binds&to&calcium&channels,&decreasing&calcium&influx&and&so&

limiting&further&transmitter&release.&

X! Norepinephrine&makes&channel&openings&less&frequent&and&of&shorter&duration&

&

Indirect(G(ProteinJChannel(Interactions(!Adenylyl(Cyclase((AC)(pathway(

X! Binding&of&norepinephrine&to&βXadrenergic&receptors&activates,&through&G&protein,&the&

enzyme&adenylyl&cyclase&&

X! Adenylyl&cyclase&catalyzes&the&conversion&

of&ATP&to&cyclic&AMP&

X! As&the&concentration&of&cyclic&AMP&

increases,&it&activates&cAMPXdependent&

protein&kinase,&and&enzyme&that&

phosphorylates&proteins.&

X! The&response&to&norepinephrine&is&

terminated&by&the&hydrolysis&of&cyclic&AMP&

to&5’XAMP&and&the&removal&of&protein&

phosphate&residues&by&protein&

phosphatases.&

X! Norepinephrine&causes&phosphorylation&of&voltageXactivated&calcium&channels,&

converting&them&to&a&form&that&can&be&opened&by&depolarization&

(Phospholipase(C((PLC)(pathway(

X! The&binding&of&norepinephrine&to&its&

receptor&activates,&through&a&G&protein,&

the&enzyme&phospholipase&C.(X! This&enzyme&hydrolyzes&the&phospholipid&

PIP2,&releasing&two&intracellular&second&

messengers:&DAG&and&IP3(X! IP3&releases&calcium&from&the&ER&into&the&

cytoplasm(X! DAG&and&calcium&together&activate&

protein&kinase&C(X! Protein&kinase&C&catalyzes&increased&

protein&phosphorylation(X! This&causes&a&decrease&in&calcium&current(

(((

Phospholipase(A2((PLA2)(pathway(X! Binding&of&FMRFamide&to&its&receptor&

activates,&through&a&G&protein,&the&enzyme&

phospholipase&A2&

X! This&enzyme&degrades&membrane&

phospholipids,&such&as&PIP2,&forming&an&

acid&

X! Arachidonic&acid&is&metabolized&along&the&

lipoxygenase&pathway&to&form&12XHPETE,&

which&binds&to&SXcurrent&potassium&

channels&and&increases&their&probability&of&

opening&(pO)&&

&

Calcium(Signaling(Pathways((((((((((((((XThe&concentration&of&calcium&in&the&cytoplasm&is&regulated&by&influx&through&membrane&

channels,&by&the&activity&of&calcium&pumps&and&exchangers&in&the&plasma&membrane,&by&

sequestration&in&internal&stores&such&as&the&ER&and&by&release&from&internal&storage&sites&by&

sodium&influx,&calcium&influx,&and&IP3.&

XCalcium,&in&turn,&regulates&membrane&and&cytosolic&proteins,&including&ion&channels,&

exchangers,&pumps,&phospholipases,&protein&kinase&C,&calmodulin&and&calpain.&

&

&

&

&

&

&

&

&

&

&

Effect(of(G(Protein(Signaling(Pathways(on(Cell(Transcription(“Long(Term(Effect”(&

(((((((((((((Activation&of&G&proteins&by&metabotropic&neurotransmitter&receptors&triggers&intracellular&

signaling&cascades&involving&PIXPLC,&AC,&Ras&and&Rac&which&activate,&in&turn,&protein&kinases.&The&

protein&kinases&phosphorylate&a&wide&variety&of&target&proteins.&Phosphorylation&of&

transcription&factors&alters&gene&expression&and&produces&longXlasting&changes&in&the&cell.&

((Transmitter)Release)Mechanism&of&Transmitter&Release&

X! PresynapticXPostsynaptic&Coupling&!&if&you&increase&one,&you&will&have&the&same&effect&

on&the&other&

X! The&normal&fluxes&of&sodium&and&potassium&ions&responsible&for&the&action&potential&are&

not&necessary&for&transmitter&release;&depolarization&is&the&trigger.&

X! One&characteristic&of&the&transmitter&release&process&is&the&synaptic(delay,&the&time&

between&the&onset&of&the&presynaptic&action&potential&and&the&beginning&of&the&synaptic&

potential.&&

X! The&time&required&for&the&presynaptic&terminal&to&depolarize&and&the&calcium&channels&

to&open&accounts&for&the&first&half&of&the&synaptic&delay;&the&time&required&for&calcium&

concentration&to&rise&within&the&terminal&and&evoke&transmitter&release&accounts&for&the&

remainder.&

&

Calcium&and&Transmitter&Release&

X! Transmitter&release&can&be&reduced&either&by&removing&calcium&from&the&bathing&

solution&or&by&adding&a&blocking&ion&

X! For&transmitter&release&to&occur,&calcium&must&be&present&in&the&bathing&solution&at&the&

time&of&depolarization&of&the&presynaptic&terminal&

X! The&calcium&conductance&of&the&membrane&is&increased&by&depolarization&and&that&

calcium&enters&with&each&action&potential&

X! Depolarization&of&the&terminal&is&not&sufficient&on&its&own&to&trigger&release;&calcium&

entry&must&also&occur&

Quantal&Release&

X! Transmitters&are&released&from&terminals&in&multimolecular&packets&called&quanta&X! In&general,&at&any&given&synapse&the&number&of&quanta&released&from&the&terminal&in&

response&to&an&action&potential&(the&quantum(content&of&a&synaptic&response)&may&vary&

considerably,&but&the&number&of&molecules&in&each&quantum&(quantum(size)&is&fixed&(with&a&variance&of&about&10%).&

X! Miniature&synaptic&potentials&occur&spontaneously&at&the&frog&neuromuscular&junction.&

After&addition&of&prostigmine,&which&prevents&acetylcholinesterase&from&hydrolyzing&

ACh,&miniature&synaptic&potentials&are&increased&in&amplitude&and&duration,&but&the&

frequency&at&which&they&occur&is&unchanged.&This&indicates&that&each&miniature&is&due&to&

a&quantal&packet&of&ACh,&rather&than&to&a&single&molecule&of&ACh.&

X! At&rest,&nerve&terminal&release&quanta&spontaneously&at&a&slow&rate,&giving&rise&to&

spontaneous&miniature&synaptic&potentials.&There&is&also&at&rest&a&continuous,&

nonquantal&leak&of&transmitter&from&nerve&terminals.&

X! In&general,&presynaptic&modulatory&effects&change&the&amount&of&transmitter&released&

by&changing&quantum&content,&not&quantum&size.&

X! On&the&other&hand,&postsynaptic&modulatory&influences&change&the&sensitivity&of&the&

postsynaptic&cell&to&transmitter&and&alter&quantum&size,&not&the&number&of&quanta&

released.&

&

&

Quantum&Content&and&Number&of&Molecules&in&Quantum&

X! Quantum&content&(number&of&quanta&released)&!&vary&

X! Quantum&size&(number&of&molecules&in&each&quantum)&!&fixed&

X! Mean&quantum&content&(m):&

o! Neuromuscular&junction&!&200X300&

o! Ganglia&!&2X20&

o! CNS&!&1&

X! Quantum&size:&

o! ACh&vesicle&!&7000&molecules&

o! Glutamate&vesicle&!&4000&molecules&

&

Number&of&Channels&Activated&by&a&Quantum&

X! Given&that&a&quantum&of&ACh&consists&of&about&7000&molecules,&only&a&few&thousand&of&

these&will&actually&combine&with&postsynaptic&receptors&at&the&neuromuscular&junction,&

the&remainder&will&be&lost&to&diffusion&out&of&the&cleft&or&hydrolysis&by&cholinesterases.&

X! The&number&of&receptors&activated&by&a&quantum&can&be&determined&by&comparing&the&

conductance&change&that&occurs&during&a&miniature&potential&with&that&produced&by&a&

single&AChXactivated&channel.&&

X! The&number&of&postsynaptic&receptors&activated&by&a&quantum&of&transmitter&released&

from&a&single&presynaptic&bouton&is&tailored&to&the&size&of&the&cell.&

X! In&large&cell&with&low&input&resistances,&a&large&number&of&receptors&must&be&activated&

for&the&effect&of&a&quantum&to&be&significant.&

X! Activation&of&the&same&number&of&receptors&on&a&very&small&cell,&on&the&other&hand,&

would&overwhelm&all&the&other&conductances,&depolarizing&the&cell&to&a&potential&near&0&

if&the&synapse&were&excitatory,&or&locking&its&membrane&potential&firmly&at&the&chloride&

equilibrium&potential&of&the&effect&were&inhibitory.&

X! The&area&of&postsynaptic&membrane&relative&to&the&size&of&a&synaptic&vesicle&

o! At&the&frog&NMJ,&ACh&receptors&are&packed&at&high&density&over&a&large&

postsynaptic&area.&Accordingly,&receptors&outnumber&ACh&molecules,&and&the&

size&of&the&quantal&event&varies&with&the&variation&in&the&number&of&molecules&

per&quantum.&(PERIPHERAL&SYNAPSE&–&1000&channels&activated)&

o! At&a&typical&hippocampal&synapse,&postsynaptic&receptors&are&packed&less&densely&

over&a&very&small&area.&As&a&result,&the&number&of&transmitter&molecules&in&a&

quantum&is&sufficient&to&saturate&the&available&receptors,&and&quantal&events&

show&very&little&fluctuation&in&amplitude.&(CENTRAL&SYNAPSE&–&15X65&channels&

activated)&

"! Synaptic&integration&

&

Vesicle&Hypothesis&of&Transmitter&Release&

X! Hypothesis&!&a&quantum&of&transmitter&corresponds&to&the&contents&of&one&vesicle&and&

that&release&occurs&by&a&process&of&exocytosis,&in&which&vesicle&fuses&with&the&presynaptic&plasma&membrane&and&releases&its&contents&into&the&synaptic&cleft&

X! Synaptic&membrane&structure&at&the&frog&NMJ&!&The&cytoplasmic&half&of&the&presynaptic&

membrane&at&the&active&zone&shows&on&its&

fracture&face&protruding&particles&whose&

counterparts&are&seen&as&pits&on&the&fracture&

face&of&the&outer&membrane&leaflet.&Vesicles&

fusing&with&the&presynaptic&membrane&give&

rise&to&pores&and&protrusions&on&the&two&

fracture&faces.&The&fractured&postsynaptic&

membrane&in&the&region&of&the&folds&shows&a&

high&concentration&of&particles&on&the&fracture&

face&of&the&cytoplasmic&leaflet;&these&are&ACh&

receptors.&

&

&

&

&

&

&

&

&

&

&

&

&

Release&and&Retrieval&of&Vesicles&

X! Release&occurs&by&the&process&of&exocytosis,&during&which&the&synaptic&vesicle&membrane&fuses&with&the&presynaptic&membrane&and&the&contents&of&the&vesicle&are&

released&into&the&synaptic&cleft.&

o! Transient&increases&in&capacitance&may&correspond&to&exocytosis&through&a&

temporary&fusion&pore&that&rapidly&closes,&allowing&the&vesicle&to&pinch&back&off&

into&the&cytoplasm&without&ever&becoming&incorporated&into&the&plasma&

membrane.&Under&such&circumstances,&small&molecules&may&be&released&while&

larger&proteins&are&retained&in&the&vesicle.&(Kiss&and&run&exocytosis)&&

&

&

&

&

&

&

&

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&

&

X! The&components&of&the&vesicle&membrane&are&then&retrieved(by&endocytosis,&sorted&into&endosomes,&and&recycled&into&new&synaptic&vesicles.&

Proposed&pathway&for&vesicle&retrieval&during&vesicle&recycling&(endocytosis):&

o! After&exocytosis,&clathrinXcoated&vesicles&selectively&recapture&synaptic&vesicle&

membrane&components.&

o! New&synaptic&vesicles&are&formed&from&

coated&vesicles,&either&directly&or&

through&endosomes.&

o! After&intense&stimulation,&retrieval&

occurs&from&uncoated&pits&and&cisternae.&

o! The&new&synaptic&vesicles&formed&from&

recycled&membrane&are&filled&with&

transmitter&and&can&be&released&by&

stimulation.&

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