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¬&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¬&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¬&establish&gap&
junctions&with&neurons.&
o! Communicate&with&neurons&by&releasing&glutamate&and&other&transmitters&
•! Radial(glia&(development)&!®ulate&development&and®eneration&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&litude&
●! 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&litude&(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®ion&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®ulate¤t&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¬&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¬&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&lifier,&small¤ts&cross&the&
patch&of&membrane&inside&the&pipette&tip&can&be&recorded&
o! The&recorded&events&consist&of&rectangular&pulses&of¤t,&reflecting&the&
opening&and&closing&of&single&channels&
o! In&graph&of&patch&clamp&recordings:&
"! Downward&deflections&indicate¤t&flowing&into&the&cell&=&inward&
current&
"! Upward&deflections&=&outward¤t&
-! Intracellular&recording&withµelectrodes&
o! A&sharp&glassµpipette,&filled&with&a&concentrated&salt&solution,&serves&as&an&
electrode&and&is&connected&to&an&lifier&to&record&the&potential&with&its&tip&
&
Channel(Conductance((XChannel¤t:&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,¤t&flows&the&other&way,&through&the&open&
channel&into&the&pipette&
XThe&relationship&is&linear:&
& I&=&γV&(Ohm’s&law)&
I&=¤t&
γ&=&channel&conductance&V&=&voltage&
*Current&directly&proportional&to&the&voltage&applied&to&it&
XIon¤t&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&–¬&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¢ral&pore&
o! 2α&subunits&–&contain&the&receptor&sites&for&ACh&(ligand)&•! Has&transmembrane,&extracellular&and&intracellular&domains&
•! Each&subunit&contains&4&membraneXspanning®ions&(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°ree&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®ions&
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¬&only&by&aa&composition&of&their&membrane&spanning&domains&but&
also&by&the&number&of&membrane&spanning®ions: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®ion&of&the&
synapse;&this&removal&helps&terminate&its&synaptic&action&and&prevents&its&diffusion&to&other&
synaptic®ions.&(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+¤t&!&Depolarization&
-! Potassium&efflux&leads&to&repolarization&
o! Depolarization&!&Increase&in&gK&!&Outward&K+¤t&!&Repolarization&
&
gNa&=&INa/&(Vm&–&ENa)&
gK&=&IK&/&(Vm&–&EK)&
g&=&conductance&
I&=¤t&
Vm&=&membrane&potential&
Vm&–&E&=&driving&force&
&
Currents&during&depolarization&
-! Brief&positive&capacitative¤t&(outward)&!&due&to&movement&of&potassium&and&
chloride&
-! Early&transient&phase&of&inward¤t&!&due&to&sodium&entry&
-! Late&maintained&outward¤t&!&due&to&potassium&movement&out&of&the&fiber&
(TTX(!&blocks&voltageXactivated&sodium&conductance&selectively;&when&poised&with&TTX,&no&
inward¤t&of&sodium&is&seen,&only&outward&potassium¤t&
&
TEA(!&blocks&voltageXactivated&potassium¤ts&
&
Effect&of&membrane&potential&on&ion¤ts&
-! Early&sodium¤t&first&increases,&then&decreases&as&depolarizing&steps&increase&
(reverses&to&outward¤t&at&around&the&Na&equilibrium&potential)&
-! Late&potassium¤t&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¤ts&are&exactly&equal&and&opposite,&just&as&they&are&at&rest&BUT&the&balance&of¤ts&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®enerative&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¤ts&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®enerative&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¤t&spreads&depends&on&the&conductivity&of&the&core&
and&the&effectiveness&of&the&insulation&in&preventing¤t&loss.&&
-! In&an&axon,¤t&is&carried&by&the&flow&of&ions&
-! The&most&abundant&small&ion&in&the&axoplasm&is&potassium,&which&therefore&carries&most&
of&the¤t&
-! 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¤t&to&leak&out&
before&it&can&spread&very&far&
-! A&largerXresistance&membrane&allows&a&greater&portion&of&the¤t&to&spread&laterally&
before&escaping&the&external&solution&
&
Resistance&
-! The&potential&change&produced&across&the&membrane&at&any&given&distance&is&
proportional&to&the¤t&flow&across&the&membrane&at&that&point&(in&accordance&with&
Ohm’s&law)&
-! The&decrease&in&potential&with&distance&from&the¤t&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¤t&
-! The&length(constant(of&the&fiber&(λ)&is&the&distance&over&which&the&potential&falls&to&1/e&(37%)&of&its&maximum&value.&
-! Two¶meters&(rinput&and&λ)&define&how&much&depolarization&is&produced&by&a&given&
amount&of¤t,&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¤t&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¤t)&
o! Decreases&with&increasing&internal&resistance&(which&resists¤t&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®ion&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¤t&spreads&longitudinally&in&the&fiber&away&from&the&active®ion&
-! Ahead&of&the&active®ion&this¤t&depolarizes&a&new&segment&of&membrane&toward&
threshold&
-! Behind&the&peak&of&the&action&potential&the&potassium&conductance&is&high&and¤t&
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®enerative&response&
cannot&occur&
-! As&the&action&potential&leaves&the®ion,&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¤t&
flow&largely&to&the&node&because&ions&cannot&flow&easily&
into&or&out&of&the&highXresistance&intermodal®ion&and&the&
intermodal&capacitative¤ts&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¬&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®enerative&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¶nodal&sheath&
&
Pathways&for¤t&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¤t&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¬&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¬&a&general&feature&of&
chemical&synapses&
•! Motor(end(plate(!®ion&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,¬&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,¤t&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¬&to&chloride&
XWith&the&muscle&membrane&potential&clamped&at&X40mV,&nerve&stimulation&produced&an&
inward¤t,&which&would&have&caused&a&depolarization&if&the&fiber&had¬&been&voltageX
clamped.&
XAt&more&negative&holding&potentials,&the&end&plate¤t&increased&in&litude.&
XWhen&the&membrane&was&polarized,&the&end&plate¤t&decreased&in&litude.&
XWith&further&depolarization,&the¤t&reversed&direction&and&was&outward.&
XThe¤t&changed&from&inward&to&outward&near&zero&membrane&potential.&Accordingly,&zero&
is&called&the&reversal(potential((Vr)(!&at&this&potential,&the&inward&sodium¤t&is&exactly&
equal&and&opposite&to&the&outward&potassium¤t&
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¤t&into&the&cell,&the&litude&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&litude.&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¤t&will&be&equal&to&the&chloride&equilibrium&potential&
XAt&membrane&potentials&positive&to&ECl&the¤t&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¬&
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®ion&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>P&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>P&to&GDP&and&inorganic&phosphate&(Pi)&by&the&endogenous>Pase&
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¤t&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&&
X! As&the&concentration&of&cyclic&&
increases,&it&activates&cAMPXdependent&
protein&kinase,&and&enzyme&that&
phosphorylates&proteins.&
X! The&response&to&norepinephrine&is&
terminated&by&the&hydrolysis&of&cyclic&&
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¤t(
(((
Phospholipase(A2((PLA2)(pathway(X! Binding&of&FMRFamide&to&its&receptor&
activates,&through&a&G&protein,&the&enzyme&
phospholipase&A2&
X! This&enzyme°rades&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®ulated&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,®ulates&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¬&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&litude&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,¬&quantum&size.&
X! On&the&other&hand,&postsynaptic&modulatory&influences&change&the&sensitivity&of&the&
postsynaptic&cell&to&transmitter&and&alter&quantum&size,¬&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&litude.&(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®ion&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)&&
&
&
&
&
&
&
&
&
&
&
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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&
&
&
&
(&