BIOL 2021 Lecture 2: Chapter 11

18 views22 pages
6 Aug 2016
Department
Course
Audio 1
Audio&recording& started:&8:33&AM&Thursday,&June&30,&2016
Membrane&transport
Transmembrane&proteins&account&for&15-30%&of&transport&mechanism.&In&some&
mammalian&cells&(nerve&and&kidney),&2/3&of&metabolic&energy&is&consumed&in&
membrane&transport.&
Table&11-1
Vast&differences&between&intra-and&extracellular& content&of&the&cell
Greatest&difference&for&calcium&-critical& -used&for&muscle&contraction,&enzyme&
function…&
Cations&and&anions&must&balance&in&and&out
Calcium&and&magnesium&inside&the&cell&is&held&by&other&molecules,&what&is&unbound&is&
said&to&be&free;&total&concentration&is&much&higher&than&free.
To&maintain&concentrations,&transporters&and&channels&are&used.
The&electrochemical& gradients&across&the&cell&membrane&creates&potential&energy&for&
the&cell.&
Drives&transport&processesA.
Conveys&electrical&signals&(action&potential)B.
Allows&bacteria,&mitochondria&and&chloroplast&to&generate&ATPC.
This&electrochemical& gradient&
Figure&11-1
Given&time,&any&molecule&will&diffuse&across&a&synthetic&lipid&bilayer&down&its&
concentration&gradient.
Size&of&molecule
-
Hydrophobicity&of&the&molecule&(hydrophilic&molecules&are&harder&to&move&
across&the&bilayer)
-
Rate&of&diffusion&vary&on&
Small&nonpolar&molecules&such&as&gases,&oxygen&carbon&dioxide&and&ammonia,&and&
some&steroids&and&hormones&can&pass&easily.
Small&uncharged&polar&molecules&such&as&water&urea,&glycerol&or&nh3&can&diffuse&but&
more&slowly.
Large&uncharged&polar&molecules&such&as&sugars&move&very&very&slowly.
Charged&molecules(hydrophilic)&such&as&ions&are&impermeable&no&matter&how&small.&
Transporters:&specific&to&the&solute,&conformational&change&on&the&protein&to&
transfer&the&solute&across&the&membrane,&there&is&a&binding&site&where&the&
solute&can&binds&to
-
Channels:&interact&with&the&solute&more&weakly,&form&continuous&pore&that&
extends&across&the&entire&bilayer,&when&channel&opens,&they&allow&specific&
solutes&(small&ions&or&small&molecules&such&as&water,&glycerol&or&nh3)&to&pass&
through&them;&the&rate&of&transport&is&much&faster&than&through&membrane&
transporters
-
Two&main&classes&of&transport&proteins&are:
Figure&11-3
Figure&11-4
All&channels&and&many&transporters&allow&solutes&to&cross&the&membrane&via&passive&
transport-down&its&concentration&gradient.&
Concentration&gradient
-
Electrical& potential&across&the&membrane&(membrane&potential)
-
If&the&solute&is&charged,&transport&is&influenced&by:
The&combined&net&driving&force&is&the&electrochemical& concentration.&
Note:&Most&cells&have&negative&potential&on&the&inside.
In&some&situations,&solutes&must&move&against&its&electrochemical&gradient&-this&is&
active&transport.&It&always&requires&energy&such&as&ion&gradient&or&ATP.&
Figure&11-5
Model&of&the&conformational&changes&in&a&transporter
Binding&site&has&to&be&exposed&for&the&solute&(outward&open&facing)1.
Solute&is&trapped,&it&cant&leave&the&transporter&transition&state&(occluded)2.
Solute&binding&site&is&exposed&on&the&inside&of&the&cell&(inward&open)3.
=>&reversible&transitions
=>&transitions&are&very&random,&can&occur&even&if&the&solute&is&not&bound
If&the&solute&concentration&is&higher&on&the&outside,&more&solute&will&bind&to&the&
transporter&in&the&outward-open&state;&so&there&is&net&transport&down&the&
concentration&gradient.&
Figure&11-6
The&process&of&solute-mediated&transport&is&similar&to&enzyme-substrate&reaction.
Simple&diffusion&or&channel-mediated&transport&is&directly&proportional&to&the&solute&
concentration&(within&a&physical&limit).
A&transporter&can&transport&a&solute&to&maximal&limit&(Vmax).&It&occurs&when&all&solute&
binding&sites&are&occupied.&
A&transporter&has&a&characteristic&affinity&for&the&solute&Km&(binding&constant).&Km&is&
equal&to&the&concentration&of&the&solute&when&the&transport&rate&is&half&maximal&
(1/2Vmax).&
Figure&11-7
Models&of&active&transport
Coupled&transport:&use&energy&stored&in&concentration&gradients&to&couple&the&
uphill&transport&of&one&solute&across&the&membrane&to&the&downhill&transport&of&
another&solute.&
-
ATP&driven&transporters&(pumps):&couple&the&uphill&transport&of&solute&to&the&
hydrolysis&of&ATP.&
-
Light&or&redox-driven&transporters&(pumps)couple&the&uphill&transport&of&the&
solute&to&an&input&of&light&or&from&a&redox&reaction;&typically&found&in&bacteria,&
archaea,&chloroplast&(light),&mitochondria&(redox)
-
Figure&11-8
Some&transporters&mediate&movement&of&a&single&solute&at&a&rate&determine&by&their&
Vmax&and&Km&=>&uniporters&(generally&used&for&&passive,&if&ATP&is&used&we&call&it&a&
pump)
Same&direction&symporter
-
Opposite&direction&antiporter
-
Other&can&couple&the&transport&of&one&solute&if&a&second&solute&is&present&=>&coupled&
transporters
Figure&11-9
Example&of&symport
Sodium-glucose&co-transporter&moves&glucose&against&its&concentration&gradient&using&
the&sodium&concentration&gradient.&
The&occluded&empty&transporter&changes&the&outward&open&state.&
Sodium&and&glucose&can&now&bind&to&their&respective&binding&sites.&Since&sodium&is&
much&higher&outside,&glucose&is&more&likely&to&bind&to&the&transporter&in&the&outward-
open&state.&
The&binding&is&cooperative-that&is&the&binding&of&one&solute&increases&transporter's&
affinity&(Km)&for&the&other&solute.&
The&transporter&transitions&to&the&occluded-occupied&state.&This&occurs&only&when&
both&sodium&and&glucose&are&bound.
The&binding&of&both&sodium&and&glucose&induces&the&conformational&change&in&the&
transporter&to&the&more&energetically& favourable&state.
From&the&occluded-occupied&state,&the&transporter&can&transition&either&back&to&the&
outward-open&state&or&inward-open&state.&
=>&If&the&transporter&goes&back&to&outward-open,&no&transport&occurs.
=>&If&transporter&moves&to&inward-open&state,&sodium&dissociates&since&concentration&
is&low.&Affinity&for&glucose&is&reduced&so&glucose&dissociates&as&a&result&of&sodium&
dissociation.&The&net&effect&is&the&transport&of&glucose.
Occluded&state&only&occurs&when&the&transport&is&fully&empty&or&completely&occupied.&
This&ensures&coupling&sodium&ad&glucose&movement.&
Figure&11-11
Example&movement&of&glucose&in&intestine
In&the&epithelial&cells&that&line&intestine,&glucose&is&transported&from&the&gut&lumen&to&
extracellular& fluid&where&it&can&pass&into&the&blood.&
There&is&an&asymmetric&distribution&of&glucose&transporters&in&gut&epithelial& cells.
Proteins&may&be&restricted&to&a&particular&membrane&domains&on&the&cell.
Epithelial& cell&have&asymmetrical&distribution&of&proteins&on&the&apical&and&basolateral&
surfaces.
On&the&apical&surface,&the&sodium&glucose&cotransporter&allows&the&movement&of&
glucose&from&the&gut&lumen&(low&concentration)&to&the&intracellular&space&(high&
concentration).&
On&the&basal&surface,&the&glucose&uniporter&moves&glucose&down&its&concentration&
gradient&into&the&extracellular&space.&
The&&accumulation&&of&sodium&inside&the&epithelial&cell& is&pumped&out&by&the&active&
transporter,&the&sodium-potassium&pump.&
Figure&11-12
ATP-driven&pumps
P-type&pumps phosphorylate&themselves&during&the&pumping&cycle.&They&include&
many&of&ion&pumps&that&are&responsible&for&setting&up&and&maintaining&ion&gradients.&
Sarcoplasmic&reticulum&Ca+&pump&found&in&muscle&cells&(contraction&of&muscle&
requires&calcium,&it&can&come&from&outside&or&can&come&from&inside&where&it&is&
stored&in&sarcoplasmic&reticulum,&taking&back&up&calcium&when&the&muscle&
relaxes)&
-
Sodium-potassium&pump&which&establishes&the&sodium&and&potassium&gradients&
across&the&plasma&membrane
-
Example
High&resolution&X-ray&crystal&structure&of&the&sarcoplasmic&reticulum&calcium&ump&and&
the&schematic&model&of&the&pump
Figure&11-13
Nucleotide-binding&domain:&where&ATP&binds1)
Phosphorylation&domain:&where&phosphate&binds&2)
Activator&domain:&transduces&the&changes&in&P-domain&and&N-domain&(senses&
changes&and&relies&them)
3)
Transmembrane&domain:&where&the&calcium&binding&site&is&located4)
Figure&11-14
The&SR&calcium&pump&undergoes&a&series&of&conformational&changes.&
ATP&binds&to&the&N&domain.&2&calcium&molecules&bind&to&transmembrane&domain,&at&
the&same&time&2H+&leave.
Conformational&change&to&occlude&the&calcium.&
ATP&is&hydrolyzed&on&the&N&domain&and&the&Pi&is&transferred&to&the&P&domain.
ADP&released.&A&new&ATP&molecule&can&then&bind&to&the&N&domain.
There&is&conformational&change&in&the&SR&Ca+&pump&to&the&inward-open&state.&2Ca+&
and&2H+&are&released.&
Audio 2
Audio&recording& started:&10:17&AM&Thursday,&June&30,&2016
Figure&11-15
A&similar&series&of&conformational&changes,&ATP&binding,&phosphorylation&and&ion&
movement&occurs&in&the&plasma&membrane&sodium&potassium&pump.&
The&sodium&potassium&moves&#&Na+&out&for&every&2K+.&Both&are&pumped&against&their&
concentration&gradient.&
Figure&11-16
ABC&(ATP&binding&cassette)&transporters&pump&small&molecules&across&the&cell&
membranes.&ABC&transporters&constitute&the&largest&family&of&membrane&domains.
ABC&transporters contain&two&highly&conserved&ATPase&domains&on&the&cytoplasmic&
side.&
The&binding&of&2&ATP&brings&the&two&ATPase&domains&together.&ATP&binding&exposes&
the&solute&binding&site&to&the&extracellular&side.&
Hydrolysis&of&ATP&separates&the&ATPase&domains&and&causes&a&conformational&change&
in&the&transporter.&
Hydrolysis&-against&concentration&gradient
V-type&proton&pumps are&turbine&like&protein&machines.
V-type&pumps&transfer&H+&into&organelles&such&as&lysosomes,&vesicles&or&vacuoles&to&
acidify&in&their&interior.&
F-ATPaseis&structurally&related&to&V-type&proton&pumps.&Instead&of&suing&ATP&
hydrolysis&to&drive&H+&transport,&they&use&H+&gradient&across&the&membrane&to&
synthesize&ATP.&
Channels&can&pass&up&to&100&million&ions&per&second,&x100000greater&than&the&fastest&
rate&of&transport&by&any&transporter.&Ion&channels&allow&the&specific&movement&of&
inorganic&ion&(primarily&sodium&potassium&calcium&or&chloride)&down&their&
electrochemical& gradients.&
Figure&11-20
Not&all&channel&are&permeable&to&ions.
Aquaporins&are&permeable&to&water&but&not&to&ions.&It&was&previously&believed&water&
moved&by&osmosis&only.&However,&some&cells&kidney&or&exocrine& glands&must&allow&the&
rapid&movement&of&water.&
They&have&a&narrow&water-filled&pore.&Water&can&move&through&the&pore&only&in&a&
single&file.
The&pore&is&made&of&carbonyl&oxygens&from&the&amino&acids&that&line&the&pore.&
The&carbonyl&oxygens&help&to&align&the&water&molecules&in&the&pore.&Carbonyl&oxygens&
form&transient&hydrogen&bonds&with&one&of&the&hydrogen&atoms&in&water.&
Aquaporin&is&impermeable&to&H+.&In&water,&H+&can&diffuse&rapidly&by&being&relayed&fro&
one&water&molecule&to&the&next.&
Two&asparagine&residues&in&the&centre&of&the&pore&of&aquaporin&tether&the&two&
valences&if&the&water&molecule&to&prevent&a&H+&relay&through&the&pore.
The&discovery&of&aquaporin
Figure&11-21
Ion&selectivity&(discriminates&what&ion&moves&through):&Ions&normally&pass&
through&the&channel&in&single&file.&Selectivity&filter&is&the&narrowest&part&of&the&
channel&and&allows&the&channel&to&discriminate&what&can&go&in.
-
Gating&(how&they&open&and&close):&channel&gating&is&the&channel&opening&and&
closing,&and&in&some&cases&inactivity.&
-
=>&voltage&(electrical& signal)
=>&ligand&(a&substance)
=>&mechanical&(stretching&the&membrane)
Ion&channels&have&two&properties:&
Figure&11-22
The&channel&pore&is&wide&on&the&outside&and&inside&of&the&channel&and&it&narrows&at&
the&selectivity&filter.&The&selectivity&filter&is&formed&by&top.&
Similar&to&aquaporin,&the&carbonyl&oxygens&in&the&selectivity&filter&play&a&role&in&ion&
movement&and&selectivity.&
Potassium&channels&are&larger&than&sodium&ions&but&potassium&channels&can&conduct&
potassium&10000fold&faster&than&sodium.&
Figure&11-23
Potassium&ions&on&solution&are&hydrated&and&surrounded&by&$&water&molecules.&In&the&
selectivity&filter,&potassium&is&fully&dehydrated.&$&carbonyl&oxygens&perfectly&
coordinate&the&with&potassium&to&replace&the&oxygen&from&water.&
Sodium&ions&are&also&hydrated&and&surrounded&by&4-6&water&molecules.&It&cannot&
coordinate&with&all&$&carbonyl&oxygens&to&replace&all& the&oxygen&from&water.&Sodium&
cannot&get&fully&dehydrated&and&is&therefore&too&large.&
Figure&11-24
Another&unique&feature&of&this&channel&is&the&pore&helix.&
The&pore&helix&points&toward&the&centre&of&the&inner&vestibule.
Peptide&bonds&have&an&electric&dipole&due&to&the&orientation&of&the&amino&and&
carboxyl&group.&
The&electric& dipole&along&the&pore&helix& is&oriented&such&tat&the&negative&dipole&faces&
toward&the&inner&vestibule.&The&negative&dipole&attracts&potassium&&towards&the&
selectivity&filter.&
The&selectivity&filter&can&accommodate&more&than&K+&ion,&multi-ion&pore.&
The&multi&occupancy&for&ion-ion&repulsion&which&contributes&to&the&high&flux&rate&(10^
7)
Ion&channel&gating&is&due&to&the&movement&of&the&inner&helix.&
Figure&11-25
Mechanosensitive&channels&open&due&to&increased&pressure&or&stretch&on&the&lipid&
membrane.&
Figure&11-30
An&action&potential&I&an&active&electrical&response&in&cells.&It&can&be&triggered&by&a&small&
depolarizing&current.&
Close1.
Open2.
Inactivated3.
The&initiation&of&the&action&potential&is&due&to&the&opening&of&voltage-gated&sodium&
channels.&Voltage&gated&sodium&channels&can&be&in&3&conformational&states&
The&closed&state&has&the&lowest&free&energy&and&is&therefore&the&most&stable&state.&
When&a&depolarizing&current&arrives&at&the&cell,&this&provides&energy&for&the&channel&to&
enter&the&open&state.&Sodium&ions&can&then&permeate&through&the&channel.&
The&opening&of&voltage-gated&channel&initiates&AP.
The&channel&can&enter&the&inactivated&state.&In&this&state,&no&sodium&can&flow&through&
the&channel.&Inactivation&of&the&voltage-gated&channels&contribute&the&to&termination&
of&AP.
The&channel&cannot&reopen&from&inactivated&state,&must&go&back&to&closed&state.&
A&subsequent&AP&will&not&occur&until&the&channel&goes&back&to&the&closed&state.&
Figure&11-29
The&structure&of&voltage&gated&sodium&channel&is&similar&to&4&voltage-gated&potassium&
channel&tethered&together.&
Figure&11-36
The&communication&between&to&neurons&occurs&at&the&synapse.&It&converts&a&chemical&
signal&into&an&electrical& signal.&The&presynaptic&nerve&terminal&comes&into&close&
proximity&to&the&postsynaptic&nerve&cell.&
The&presynaptic&nerve&terminal&contains&neurotransmitter&molecules&inside&synaptic&
vesicles.&An&AP&in&the&presynaptic&nerve&terminal&will&cause&the&release&of&
neurotransmitters&into&the&synaptic&cleft.&
The&neurotransmitter&may&bind&to&receptors&or&open&ligand-gated&channels.&This&will&&
alter&the&membrane&potential&of&the&postsynaptic&terminal.&
Figure&11-37
Figure&11-38
Ach&receptor/channel&is&a&pentameric&protein&complex.&
Comprised&of&2&alpha,&1&beta,&1&delta&and&1&gamma&subunit.&The&neurotransmitter&Ach&
binds&to&each&of&the&alpha&subunits.
When&Ach&binds&to&each&of&the&alpha&subunits,&it&causes&a&conformational&change&un&
the&transmembrane&alpha&helices.&This&leads&to&the&opening&of&the&channel&gate.&
Figure&11-34
The&patch&clamp&technique&allows&scientists&to&measure&the&activity&of&a&single&ion&
channel&in&a&living&cell&in&real&time.&
Chapter(11
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Audio 1
Audio&recording& started:&8:33&AM&Thursday,&June&30,&2016
Membrane&transport
Transmembrane&proteins&account&for&15-30%&of&transport&mechanism.&In&some&
mammalian&cells&(nerve&and&kidney),&2/3&of&metabolic&energy&is&consumed&in&
membrane&transport.&
Table&11-1
Vast&differences&between&intra-and&extracellular& content&of&the&cell
Greatest&difference&for&calcium&-critical& -used&for&muscle&contraction,&enzyme&
function…&
Cations&and&anions&must&balance&in&and&out
Calcium&and&magnesium&inside&the&cell&is&held&by&other&molecules,&what&is&unbound&is&
said&to&be&free;&total&concentration&is&much&higher&than&free.
To&maintain&concentrations,&transporters&and&channels&are&used.
The&electrochemical& gradients&across&the&cell&membrane&creates&potential&energy&for&
the&cell.&
Drives&transport&processesA.
Conveys&electrical&signals&(action&potential)B.
Allows&bacteria,&mitochondria&and&chloroplast&to&generate&ATPC.
This&electrochemical& gradient&
Figure&11-1
Given&time,&any&molecule&will&diffuse&across&a&synthetic&lipid&bilayer&down&its&
concentration&gradient.
Size&of&molecule
-
Hydrophobicity&of&the&molecule&(hydrophilic&molecules&are&harder&to&move&
across&the&bilayer)
-
Rate&of&diffusion&vary&on&
Small&nonpolar&molecules&such&as&gases,&oxygen&carbon&dioxide&and&ammonia,&and&
some&steroids&and&hormones&can&pass&easily.
Small&uncharged&polar&molecules&such&as&water&urea,&glycerol&or&nh3&can&diffuse&but&
more&slowly.
Large&uncharged&polar&molecules&such&as&sugars&move&very&very&slowly.
Charged&molecules(hydrophilic)&such&as&ions&are&impermeable&no&matter&how&small.&
Transporters:&specific&to&the&solute,&conformational&change&on&the&protein&to&
transfer&the&solute&across&the&membrane,&there&is&a&binding&site&where&the&
solute&can&binds&to
-
Channels:&interact&with&the&solute&more&weakly,&form&continuous&pore&that&
extends&across&the&entire&bilayer,&when&channel&opens,&they&allow&specific&
solutes&(small&ions&or&small&molecules&such&as&water,&glycerol&or&nh3)&to&pass&
through&them;&the&rate&of&transport&is&much&faster&than&through&membrane&
transporters
-
Two&main&classes&of&transport&proteins&are:
Figure&11-3
Figure&11-4
All&channels&and&many&transporters&allow&solutes&to&cross&the&membrane&via&passive&
transport-down&its&concentration&gradient.&
Concentration&gradient
-
Electrical& potential&across&the&membrane&(membrane&potential)
-
If&the&solute&is&charged,&transport&is&influenced&by:
The&combined&net&driving&force&is&the&electrochemical& concentration.&
Note:&Most&cells&have&negative&potential&on&the&inside.
In&some&situations,&solutes&must&move&against&its&electrochemical&gradient&-this&is&
active&transport.&It&always&requires&energy&such&as&ion&gradient&or&ATP.&
Figure&11-5
Model&of&the&conformational&changes&in&a&transporter
Binding&site&has&to&be&exposed&for&the&solute&(outward&open&facing)1.
Solute&is&trapped,&it&cant&leave&the&transporter&transition&state&(occluded)2.
Solute&binding&site&is&exposed&on&the&inside&of&the&cell&(inward&open)3.
=>&reversible&transitions
=>&transitions&are&very&random,&can&occur&even&if&the&solute&is&not&bound
If&the&solute&concentration&is&higher&on&the&outside,&more&solute&will&bind&to&the&
transporter&in&the&outward-open&state;&so&there&is&net&transport&down&the&
concentration&gradient.&
Figure&11-6
The&process&of&solute-mediated&transport&is&similar&to&enzyme-substrate&reaction.
Simple&diffusion&or&channel-mediated&transport&is&directly&proportional&to&the&solute&
concentration&(within&a&physical&limit).
A&transporter&can&transport&a&solute&to&maximal&limit&(Vmax).&It&occurs&when&all&solute&
binding&sites&are&occupied.&
A&transporter&has&a&characteristic&affinity&for&the&solute&Km&(binding&constant).&Km&is&
equal&to&the&concentration&of&the&solute&when&the&transport&rate&is&half&maximal&
(1/2Vmax).&
Figure&11-7
Models&of&active&transport
Coupled&transport:&use&energy&stored&in&concentration&gradients&to&couple&the&
uphill&transport&of&one&solute&across&the&membrane&to&the&downhill&transport&of&
another&solute.&
-
ATP&driven&transporters&(pumps):&couple&the&uphill&transport&of&solute&to&the&
hydrolysis&of&ATP.&
-
Light&or&redox-driven&transporters&(pumps)couple&the&uphill&transport&of&the&
solute&to&an&input&of&light&or&from&a&redox&reaction;&typically&found&in&bacteria,&
archaea,&chloroplast&(light),&mitochondria&(redox)
-
Figure&11-8
Some&transporters&mediate&movement&of&a&single&solute&at&a&rate&determine&by&their&
Vmax&and&Km&=>&uniporters&(generally&used&for&&passive,&if&ATP&is&used&we&call&it&a&
pump)
Same&direction&symporter
-
Opposite&direction&antiporter
-
Other&can&couple&the&transport&of&one&solute&if&a&second&solute&is&present&=>&coupled&
transporters
Figure&11-9
Example&of&symport
Sodium-glucose&co-transporter&moves&glucose&against&its&concentration&gradient&using&
the&sodium&concentration&gradient.&
The&occluded&empty&transporter&changes&the&outward&open&state.&
Sodium&and&glucose&can&now&bind&to&their&respective&binding&sites.&Since&sodium&is&
much&higher&outside,&glucose&is&more&likely&to&bind&to&the&transporter&in&the&outward-
open&state.&
The&binding&is&cooperative-that&is&the&binding&of&one&solute&increases&transporter's&
affinity&(Km)&for&the&other&solute.&
The&transporter&transitions&to&the&occluded-occupied&state.&This&occurs&only&when&
both&sodium&and&glucose&are&bound.
The&binding&of&both&sodium&and&glucose&induces&the&conformational&change&in&the&
transporter&to&the&more&energetically& favourable&state.
From&the&occluded-occupied&state,&the&transporter&can&transition&either&back&to&the&
outward-open&state&or&inward-open&state.&
=>&If&the&transporter&goes&back&to&outward-open,&no&transport&occurs.
=>&If&transporter&moves&to&inward-open&state,&sodium&dissociates&since&concentration&
is&low.&Affinity&for&glucose&is&reduced&so&glucose&dissociates&as&a&result&of&sodium&
dissociation.&The&net&effect&is&the&transport&of&glucose.
Occluded&state&only&occurs&when&the&transport&is&fully&empty&or&completely&occupied.&
This&ensures&coupling&sodium&ad&glucose&movement.&
Figure&11-11
Example&movement&of&glucose&in&intestine
In&the&epithelial&cells&that&line&intestine,&glucose&is&transported&from&the&gut&lumen&to&
extracellular& fluid&where&it&can&pass&into&the&blood.&
There&is&an&asymmetric&distribution&of&glucose&transporters&in&gut&epithelial& cells.
Proteins&may&be&restricted&to&a&particular&membrane&domains&on&the&cell.
Epithelial& cell&have&asymmetrical&distribution&of&proteins&on&the&apical&and&basolateral&
surfaces.
On&the&apical&surface,&the&sodium&glucose&cotransporter&allows&the&movement&of&
glucose&from&the&gut&lumen&(low&concentration)&to&the&intracellular&space&(high&
concentration).&
On&the&basal&surface,&the&glucose&uniporter&moves&glucose&down&its&concentration&
gradient&into&the&extracellular&space.&
The&&accumulation&&of&sodium&inside&the&epithelial&cell& is&pumped&out&by&the&active&
transporter,&the&sodium-potassium&pump.&
Figure&11-12
ATP-driven&pumps
P-type&pumps phosphorylate&themselves&during&the&pumping&cycle.&They&include&
many&of&ion&pumps&that&are&responsible&for&setting&up&and&maintaining&ion&gradients.&
Sarcoplasmic&reticulum&Ca+&pump&found&in&muscle&cells&(contraction&of&muscle&
requires&calcium,&it&can&come&from&outside&or&can&come&from&inside&where&it&is&
stored&in&sarcoplasmic&reticulum,&taking&back&up&calcium&when&the&muscle&
relaxes)&
-
Sodium-potassium&pump&which&establishes&the&sodium&and&potassium&gradients&
across&the&plasma&membrane
-
Example
High&resolution&X-ray&crystal&structure&of&the&sarcoplasmic&reticulum&calcium&ump&and&
the&schematic&model&of&the&pump
Figure&11-13
Nucleotide-binding&domain:&where&ATP&binds1)
Phosphorylation&domain:&where&phosphate&binds&2)
Activator&domain:&transduces&the&changes&in&P-domain&and&N-domain&(senses&
changes&and&relies&them)
3)
Transmembrane&domain:&where&the&calcium&binding&site&is&located4)
Figure&11-14
The&SR&calcium&pump&undergoes&a&series&of&conformational&changes.&
ATP&binds&to&the&N&domain.&2&calcium&molecules&bind&to&transmembrane&domain,&at&
the&same&time&2H+&leave.
Conformational&change&to&occlude&the&calcium.&
ATP&is&hydrolyzed&on&the&N&domain&and&the&Pi&is&transferred&to&the&P&domain.
ADP&released.&A&new&ATP&molecule&can&then&bind&to&the&N&domain.
There&is&conformational&change&in&the&SR&Ca+&pump&to&the&inward-open&state.&2Ca+&
and&2H+&are&released.&
Audio 2
Audio&recording& started:&10:17&AM&Thursday,&June&30,&2016
Figure&11-15
A&similar&series&of&conformational&changes,&ATP&binding,&phosphorylation&and&ion&
movement&occurs&in&the&plasma&membrane&sodium&potassium&pump.&
The&sodium&potassium&moves&#&Na+&out&for&every&2K+.&Both&are&pumped&against&their&
concentration&gradient.&
Figure&11-16
ABC&(ATP&binding&cassette)&transporters&pump&small&molecules&across&the&cell&
membranes.&ABC&transporters&constitute&the&largest&family&of&membrane&domains.
ABC&transporters contain&two&highly&conserved&ATPase&domains&on&the&cytoplasmic&
side.&
The&binding&of&2&ATP&brings&the&two&ATPase&domains&together.&ATP&binding&exposes&
the&solute&binding&site&to&the&extracellular&side.&
Hydrolysis&of&ATP&separates&the&ATPase&domains&and&causes&a&conformational&change&
in&the&transporter.&
Hydrolysis&-against&concentration&gradient
V-type&proton&pumps are&turbine&like&protein&machines.
V-type&pumps&transfer&H+&into&organelles&such&as&lysosomes,&vesicles&or&vacuoles&to&
acidify&in&their&interior.&
F-ATPaseis&structurally&related&to&V-type&proton&pumps.&Instead&of&suing&ATP&
hydrolysis&to&drive&H+&transport,&they&use&H+&gradient&across&the&membrane&to&
synthesize&ATP.&
Channels&can&pass&up&to&100&million&ions&per&second,&x100000greater&than&the&fastest&
rate&of&transport&by&any&transporter.&Ion&channels&allow&the&specific&movement&of&
inorganic&ion&(primarily&sodium&potassium&calcium&or&chloride)&down&their&
electrochemical& gradients.&
Figure&11-20
Not&all&channel&are&permeable&to&ions.
Aquaporins&are&permeable&to&water&but&not&to&ions.&It&was&previously&believed&water&
moved&by&osmosis&only.&However,&some&cells&kidney&or&exocrine& glands&must&allow&the&
rapid&movement&of&water.&
They&have&a&narrow&water-filled&pore.&Water&can&move&through&the&pore&only&in&a&
single&file.
The&pore&is&made&of&carbonyl&oxygens&from&the&amino&acids&that&line&the&pore.&
The&carbonyl&oxygens&help&to&align&the&water&molecules&in&the&pore.&Carbonyl&oxygens&
form&transient&hydrogen&bonds&with&one&of&the&hydrogen&atoms&in&water.&
Aquaporin&is&impermeable&to&H+.&In&water,&H+&can&diffuse&rapidly&by&being&relayed&fro&
one&water&molecule&to&the&next.&
Two&asparagine&residues&in&the&centre&of&the&pore&of&aquaporin&tether&the&two&
valences&if&the&water&molecule&to&prevent&a&H+&relay&through&the&pore.
The&discovery&of&aquaporin
Figure&11-21
Ion&selectivity&(discriminates&what&ion&moves&through):&Ions&normally&pass&
through&the&channel&in&single&file.&Selectivity&filter&is&the&narrowest&part&of&the&
channel&and&allows&the&channel&to&discriminate&what&can&go&in.
-
Gating&(how&they&open&and&close):&channel&gating&is&the&channel&opening&and&
closing,&and&in&some&cases&inactivity.&
-
=>&voltage&(electrical& signal)
=>&ligand&(a&substance)
=>&mechanical&(stretching&the&membrane)
Ion&channels&have&two&properties:&
Figure&11-22
The&channel&pore&is&wide&on&the&outside&and&inside&of&the&channel&and&it&narrows&at&
the&selectivity&filter.&The&selectivity&filter&is&formed&by&top.&
Similar&to&aquaporin,&the&carbonyl&oxygens&in&the&selectivity&filter&play&a&role&in&ion&
movement&and&selectivity.&
Potassium&channels&are&larger&than&sodium&ions&but&potassium&channels&can&conduct&
potassium&10000fold&faster&than&sodium.&
Figure&11-23
Potassium&ions&on&solution&are&hydrated&and&surrounded&by&$&water&molecules.&In&the&
selectivity&filter,&potassium&is&fully&dehydrated.&$&carbonyl&oxygens&perfectly&
coordinate&the&with&potassium&to&replace&the&oxygen&from&water.&
Sodium&ions&are&also&hydrated&and&surrounded&by&4-6&water&molecules.&It&cannot&
coordinate&with&all&$&carbonyl&oxygens&to&replace&all& the&oxygen&from&water.&Sodium&
cannot&get&fully&dehydrated&and&is&therefore&too&large.&
Figure&11-24
Another&unique&feature&of&this&channel&is&the&pore&helix.&
The&pore&helix&points&toward&the&centre&of&the&inner&vestibule.
Peptide&bonds&have&an&electric&dipole&due&to&the&orientation&of&the&amino&and&
carboxyl&group.&
The&electric& dipole&along&the&pore&helix& is&oriented&such&tat&the&negative&dipole&faces&
toward&the&inner&vestibule.&The&negative&dipole&attracts&potassium&&towards&the&
selectivity&filter.&
The&selectivity&filter&can&accommodate&more&than&K+&ion,&multi-ion&pore.&
The&multi&occupancy&for&ion-ion&repulsion&which&contributes&to&the&high&flux&rate&(10^
7)
Ion&channel&gating&is&due&to&the&movement&of&the&inner&helix.&
Figure&11-25
Mechanosensitive&channels&open&due&to&increased&pressure&or&stretch&on&the&lipid&
membrane.&
Figure&11-30
An&action&potential&I&an&active&electrical&response&in&cells.&It&can&be&triggered&by&a&small&
depolarizing&current.&
Close1.
Open2.
Inactivated3.
The&initiation&of&the&action&potential&is&due&to&the&opening&of&voltage-gated&sodium&
channels.&Voltage&gated&sodium&channels&can&be&in&3&conformational&states&
The&closed&state&has&the&lowest&free&energy&and&is&therefore&the&most&stable&state.&
When&a&depolarizing&current&arrives&at&the&cell,&this&provides&energy&for&the&channel&to&
enter&the&open&state.&Sodium&ions&can&then&permeate&through&the&channel.&
The&opening&of&voltage-gated&channel&initiates&AP.
The&channel&can&enter&the&inactivated&state.&In&this&state,&no&sodium&can&flow&through&
the&channel.&Inactivation&of&the&voltage-gated&channels&contribute&the&to&termination&
of&AP.
The&channel&cannot&reopen&from&inactivated&state,&must&go&back&to&closed&state.&
A&subsequent&AP&will&not&occur&until&the&channel&goes&back&to&the&closed&state.&
Figure&11-29
The&structure&of&voltage&gated&sodium&channel&is&similar&to&4&voltage-gated&potassium&
channel&tethered&together.&
Figure&11-36
The&communication&between&to&neurons&occurs&at&the&synapse.&It&converts&a&chemical&
signal&into&an&electrical& signal.&The&presynaptic&nerve&terminal&comes&into&close&
proximity&to&the&postsynaptic&nerve&cell.&
The&presynaptic&nerve&terminal&contains&neurotransmitter&molecules&inside&synaptic&
vesicles.&An&AP&in&the&presynaptic&nerve&terminal&will&cause&the&release&of&
neurotransmitters&into&the&synaptic&cleft.&
The&neurotransmitter&may&bind&to&receptors&or&open&ligand-gated&channels.&This&will&&
alter&the&membrane&potential&of&the&postsynaptic&terminal.&
Figure&11-37
Figure&11-38
Ach&receptor/channel&is&a&pentameric&protein&complex.&
Comprised&of&2&alpha,&1&beta,&1&delta&and&1&gamma&subunit.&The&neurotransmitter&Ach&
binds&to&each&of&the&alpha&subunits.
When&Ach&binds&to&each&of&the&alpha&subunits,&it&causes&a&conformational&change&un&
the&transmembrane&alpha&helices.&This&leads&to&the&opening&of&the&channel&gate.&
Figure&11-34
The&patch&clamp&technique&allows&scientists&to&measure&the&activity&of&a&single&ion&
channel&in&a&living&cell&in&real&time.&
Chapter(11
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Audio 1
Audio&recording& started:&8:33&AM&Thursday,&June&30,&2016
Membrane&transport
Transmembrane&proteins&account&for&15-30%&of&transport&mechanism.&In&some&
mammalian&cells&(nerve&and&kidney),&2/3&of&metabolic&energy&is&consumed&in&
membrane&transport.&
Table&11-1
Vast&differences&between&intra-and&extracellular& content&of&the&cell
Greatest&difference&for&calcium&-critical& -used&for&muscle&contraction,&enzyme&
function…&
Cations&and&anions&must&balance&in&and&out
To&maintain&concentrations,&transporters&and&channels&are&used.
The&electrochemical& gradients&across&the&cell&membrane&creates&potential&energy&for&
the&cell.&
Drives&transport&processes
A.
Conveys&electrical&signals&(action&potential)
B.
Allows&bacteria,&mitochondria&and&chloroplast&to&generate&ATP
C.
This&electrochemical& gradient&
Figure&11-1
Given&time,&any&molecule&will&diffuse&across&a&synthetic&lipid&bilayer&down&its&
concentration&gradient.
Size&of&molecule
-
Hydrophobicity&of&the&molecule&(hydrophilic&molecules&are&harder&to&move&
across&the&bilayer)
-
Rate&of&diffusion&vary&on&
Small&nonpolar&molecules&such&as&gases,&oxygen&carbon&dioxide&and&ammonia,&and&
some&steroids&and&hormones&can&pass&easily.
Small&uncharged&polar&molecules&such&as&water&urea,&glycerol&or&nh3&can&diffuse&but&
more&slowly.
Large&uncharged&polar&molecules&such&as&sugars&move&very&very&slowly.
Charged&molecules(hydrophilic)&such&as&ions&are&impermeable&no&matter&how&small.&
Transporters:&specific&to&the&solute,&conformational&change&on&the&protein&to&
transfer&the&solute&across&the&membrane,&there&is&a&binding&site&where&the&
solute&can&binds&to
-
Channels:&interact&with&the&solute&more&weakly,&form&continuous&pore&that&
extends&across&the&entire&bilayer,&when&channel&opens,&they&allow&specific&
solutes&(small&ions&or&small&molecules&such&as&water,&glycerol&or&nh3)&to&pass&
through&them;&the&rate&of&transport&is&much&faster&than&through&membrane&
transporters
-
Two&main&classes&of&transport&proteins&are:
Figure&11-3
Figure&11-4
All&channels&and&many&transporters&allow&solutes&to&cross&the&membrane&via&passive&
transport-down&its&concentration&gradient.&
Concentration&gradient
-
Electrical& potential&across&the&membrane&(membrane&potential)
-
If&the&solute&is&charged,&transport&is&influenced&by:
The&combined&net&driving&force&is&the&electrochemical& concentration.&
Note:&Most&cells&have&negative&potential&on&the&inside.
In&some&situations,&solutes&must&move&against&its&electrochemical&gradient&-this&is&
active&transport.&It&always&requires&energy&such&as&ion&gradient&or&ATP.&
Figure&11-5
Model&of&the&conformational&changes&in&a&transporter
Binding&site&has&to&be&exposed&for&the&solute&(outward&open&facing)1.
Solute&is&trapped,&it&cant&leave&the&transporter&transition&state&(occluded)2.
Solute&binding&site&is&exposed&on&the&inside&of&the&cell&(inward&open)3.
=>&reversible&transitions
=>&transitions&are&very&random,&can&occur&even&if&the&solute&is&not&bound
If&the&solute&concentration&is&higher&on&the&outside,&more&solute&will&bind&to&the&
transporter&in&the&outward-open&state;&so&there&is&net&transport&down&the&
concentration&gradient.&
Figure&11-6
The&process&of&solute-mediated&transport&is&similar&to&enzyme-substrate&reaction.
Simple&diffusion&or&channel-mediated&transport&is&directly&proportional&to&the&solute&
concentration&(within&a&physical&limit).
A&transporter&can&transport&a&solute&to&maximal&limit&(Vmax).&It&occurs&when&all&solute&
binding&sites&are&occupied.&
A&transporter&has&a&characteristic&affinity&for&the&solute&Km&(binding&constant).&Km&is&
equal&to&the&concentration&of&the&solute&when&the&transport&rate&is&half&maximal&
(1/2Vmax).&
Figure&11-7
Models&of&active&transport
Coupled&transport:&use&energy&stored&in&concentration&gradients&to&couple&the&
uphill&transport&of&one&solute&across&the&membrane&to&the&downhill&transport&of&
another&solute.&
-
ATP&driven&transporters&(pumps):&couple&the&uphill&transport&of&solute&to&the&
hydrolysis&of&ATP.&
-
Light&or&redox-driven&transporters&(pumps)couple&the&uphill&transport&of&the&
solute&to&an&input&of&light&or&from&a&redox&reaction;&typically&found&in&bacteria,&
archaea,&chloroplast&(light),&mitochondria&(redox)
-
Figure&11-8
Some&transporters&mediate&movement&of&a&single&solute&at&a&rate&determine&by&their&
Vmax&and&Km&=>&uniporters&(generally&used&for&&passive,&if&ATP&is&used&we&call&it&a&
pump)
Same&direction&symporter
-
Opposite&direction&antiporter
-
Other&can&couple&the&transport&of&one&solute&if&a&second&solute&is&present&=>&coupled&
transporters
Figure&11-9
Example&of&symport
Sodium-glucose&co-transporter&moves&glucose&against&its&concentration&gradient&using&
the&sodium&concentration&gradient.&
The&occluded&empty&transporter&changes&the&outward&open&state.&
Sodium&and&glucose&can&now&bind&to&their&respective&binding&sites.&Since&sodium&is&
much&higher&outside,&glucose&is&more&likely&to&bind&to&the&transporter&in&the&outward-
open&state.&
The&binding&is&cooperative-that&is&the&binding&of&one&solute&increases&transporter's&
affinity&(Km)&for&the&other&solute.&
The&transporter&transitions&to&the&occluded-occupied&state.&This&occurs&only&when&
both&sodium&and&glucose&are&bound.
The&binding&of&both&sodium&and&glucose&induces&the&conformational&change&in&the&
transporter&to&the&more&energetically& favourable&state.
From&the&occluded-occupied&state,&the&transporter&can&transition&either&back&to&the&
outward-open&state&or&inward-open&state.&
=>&If&the&transporter&goes&back&to&outward-open,&no&transport&occurs.
=>&If&transporter&moves&to&inward-open&state,&sodium&dissociates&since&concentration&
is&low.&Affinity&for&glucose&is&reduced&so&glucose&dissociates&as&a&result&of&sodium&
dissociation.&The&net&effect&is&the&transport&of&glucose.
Occluded&state&only&occurs&when&the&transport&is&fully&empty&or&completely&occupied.&
This&ensures&coupling&sodium&ad&glucose&movement.&
Figure&11-11
Example&movement&of&glucose&in&intestine
In&the&epithelial&cells&that&line&intestine,&glucose&is&transported&from&the&gut&lumen&to&
extracellular& fluid&where&it&can&pass&into&the&blood.&
There&is&an&asymmetric&distribution&of&glucose&transporters&in&gut&epithelial& cells.
Proteins&may&be&restricted&to&a&particular&membrane&domains&on&the&cell.
Epithelial& cell&have&asymmetrical&distribution&of&proteins&on&the&apical&and&basolateral&
surfaces.
On&the&apical&surface,&the&sodium&glucose&cotransporter&allows&the&movement&of&
glucose&from&the&gut&lumen&(low&concentration)&to&the&intracellular&space&(high&
concentration).&
On&the&basal&surface,&the&glucose&uniporter&moves&glucose&down&its&concentration&
gradient&into&the&extracellular&space.&
The&&accumulation&&of&sodium&inside&the&epithelial&cell& is&pumped&out&by&the&active&
transporter,&the&sodium-potassium&pump.&
Figure&11-12
ATP-driven&pumps
P-type&pumps phosphorylate&themselves&during&the&pumping&cycle.&They&include&
many&of&ion&pumps&that&are&responsible&for&setting&up&and&maintaining&ion&gradients.&
Sarcoplasmic&reticulum&Ca+&pump&found&in&muscle&cells&(contraction&of&muscle&
requires&calcium,&it&can&come&from&outside&or&can&come&from&inside&where&it&is&
stored&in&sarcoplasmic&reticulum,&taking&back&up&calcium&when&the&muscle&
relaxes)&
-
Sodium-potassium&pump&which&establishes&the&sodium&and&potassium&gradients&
across&the&plasma&membrane
-
Example
High&resolution&X-ray&crystal&structure&of&the&sarcoplasmic&reticulum&calcium&ump&and&
the&schematic&model&of&the&pump
Figure&11-13
Nucleotide-binding&domain:&where&ATP&binds1)
Phosphorylation&domain:&where&phosphate&binds&2)
Activator&domain:&transduces&the&changes&in&P-domain&and&N-domain&(senses&
changes&and&relies&them)
3)
Transmembrane&domain:&where&the&calcium&binding&site&is&located4)
Figure&11-14
The&SR&calcium&pump&undergoes&a&series&of&conformational&changes.&
ATP&binds&to&the&N&domain.&2&calcium&molecules&bind&to&transmembrane&domain,&at&
the&same&time&2H+&leave.
Conformational&change&to&occlude&the&calcium.&
ATP&is&hydrolyzed&on&the&N&domain&and&the&Pi&is&transferred&to&the&P&domain.
ADP&released.&A&new&ATP&molecule&can&then&bind&to&the&N&domain.
There&is&conformational&change&in&the&SR&Ca+&pump&to&the&inward-open&state.&2Ca+&
and&2H+&are&released.&
Audio 2
Audio&recording& started:&10:17&AM&Thursday,&June&30,&2016
Figure&11-15
A&similar&series&of&conformational&changes,&ATP&binding,&phosphorylation&and&ion&
movement&occurs&in&the&plasma&membrane&sodium&potassium&pump.&
The&sodium&potassium&moves&#&Na+&out&for&every&2K+.&Both&are&pumped&against&their&
concentration&gradient.&
Figure&11-16
ABC&(ATP&binding&cassette)&transporters&pump&small&molecules&across&the&cell&
membranes.&ABC&transporters&constitute&the&largest&family&of&membrane&domains.
ABC&transporters contain&two&highly&conserved&ATPase&domains&on&the&cytoplasmic&
side.&
The&binding&of&2&ATP&brings&the&two&ATPase&domains&together.&ATP&binding&exposes&
the&solute&binding&site&to&the&extracellular&side.&
Hydrolysis&of&ATP&separates&the&ATPase&domains&and&causes&a&conformational&change&
in&the&transporter.&
Hydrolysis&-against&concentration&gradient
V-type&proton&pumps are&turbine&like&protein&machines.
V-type&pumps&transfer&H+&into&organelles&such&as&lysosomes,&vesicles&or&vacuoles&to&
acidify&in&their&interior.&
F-ATPaseis&structurally&related&to&V-type&proton&pumps.&Instead&of&suing&ATP&
hydrolysis&to&drive&H+&transport,&they&use&H+&gradient&across&the&membrane&to&
synthesize&ATP.&
Channels&can&pass&up&to&100&million&ions&per&second,&x100000greater&than&the&fastest&
rate&of&transport&by&any&transporter.&Ion&channels&allow&the&specific&movement&of&
inorganic&ion&(primarily&sodium&potassium&calcium&or&chloride)&down&their&
electrochemical& gradients.&
Figure&11-20
Not&all&channel&are&permeable&to&ions.
Aquaporins&are&permeable&to&water&but&not&to&ions.&It&was&previously&believed&water&
moved&by&osmosis&only.&However,&some&cells&kidney&or&exocrine& glands&must&allow&the&
rapid&movement&of&water.&
They&have&a&narrow&water-filled&pore.&Water&can&move&through&the&pore&only&in&a&
single&file.
The&pore&is&made&of&carbonyl&oxygens&from&the&amino&acids&that&line&the&pore.&
The&carbonyl&oxygens&help&to&align&the&water&molecules&in&the&pore.&Carbonyl&oxygens&
form&transient&hydrogen&bonds&with&one&of&the&hydrogen&atoms&in&water.&
Aquaporin&is&impermeable&to&H+.&In&water,&H+&can&diffuse&rapidly&by&being&relayed&fro&
one&water&molecule&to&the&next.&
Two&asparagine&residues&in&the&centre&of&the&pore&of&aquaporin&tether&the&two&
valences&if&the&water&molecule&to&prevent&a&H+&relay&through&the&pore.
The&discovery&of&aquaporin
Figure&11-21
Ion&selectivity&(discriminates&what&ion&moves&through):&Ions&normally&pass&
through&the&channel&in&single&file.&Selectivity&filter&is&the&narrowest&part&of&the&
channel&and&allows&the&channel&to&discriminate&what&can&go&in.
-
Gating&(how&they&open&and&close):&channel&gating&is&the&channel&opening&and&
closing,&and&in&some&cases&inactivity.&
-
=>&voltage&(electrical& signal)
=>&ligand&(a&substance)
=>&mechanical&(stretching&the&membrane)
Ion&channels&have&two&properties:&
Figure&11-22
The&channel&pore&is&wide&on&the&outside&and&inside&of&the&channel&and&it&narrows&at&
the&selectivity&filter.&The&selectivity&filter&is&formed&by&top.&
Similar&to&aquaporin,&the&carbonyl&oxygens&in&the&selectivity&filter&play&a&role&in&ion&
movement&and&selectivity.&
Potassium&channels&are&larger&than&sodium&ions&but&potassium&channels&can&conduct&
potassium&10000fold&faster&than&sodium.&
Figure&11-23
Potassium&ions&on&solution&are&hydrated&and&surrounded&by&$&water&molecules.&In&the&
selectivity&filter,&potassium&is&fully&dehydrated.&$&carbonyl&oxygens&perfectly&
coordinate&the&with&potassium&to&replace&the&oxygen&from&water.&
Sodium&ions&are&also&hydrated&and&surrounded&by&4-6&water&molecules.&It&cannot&
coordinate&with&all&$&carbonyl&oxygens&to&replace&all& the&oxygen&from&water.&Sodium&
cannot&get&fully&dehydrated&and&is&therefore&too&large.&
Figure&11-24
Another&unique&feature&of&this&channel&is&the&pore&helix.&
The&pore&helix&points&toward&the&centre&of&the&inner&vestibule.
Peptide&bonds&have&an&electric&dipole&due&to&the&orientation&of&the&amino&and&
carboxyl&group.&
The&electric& dipole&along&the&pore&helix& is&oriented&such&tat&the&negative&dipole&faces&
toward&the&inner&vestibule.&The&negative&dipole&attracts&potassium&&towards&the&
selectivity&filter.&
The&selectivity&filter&can&accommodate&more&than&K+&ion,&multi-ion&pore.&
The&multi&occupancy&for&ion-ion&repulsion&which&contributes&to&the&high&flux&rate&(10^
7)
Ion&channel&gating&is&due&to&the&movement&of&the&inner&helix.&
Figure&11-25
Mechanosensitive&channels&open&due&to&increased&pressure&or&stretch&on&the&lipid&
membrane.&
Figure&11-30
An&action&potential&I&an&active&electrical&response&in&cells.&It&can&be&triggered&by&a&small&
depolarizing&current.&
Close1.
Open2.
Inactivated3.
The&initiation&of&the&action&potential&is&due&to&the&opening&of&voltage-gated&sodium&
channels.&Voltage&gated&sodium&channels&can&be&in&3&conformational&states&
The&closed&state&has&the&lowest&free&energy&and&is&therefore&the&most&stable&state.&
When&a&depolarizing&current&arrives&at&the&cell,&this&provides&energy&for&the&channel&to&
enter&the&open&state.&Sodium&ions&can&then&permeate&through&the&channel.&
The&opening&of&voltage-gated&channel&initiates&AP.
The&channel&can&enter&the&inactivated&state.&In&this&state,&no&sodium&can&flow&through&
the&channel.&Inactivation&of&the&voltage-gated&channels&contribute&the&to&termination&
of&AP.
The&channel&cannot&reopen&from&inactivated&state,&must&go&back&to&closed&state.&
A&subsequent&AP&will&not&occur&until&the&channel&goes&back&to&the&closed&state.&
Figure&11-29
The&structure&of&voltage&gated&sodium&channel&is&similar&to&4&voltage-gated&potassium&
channel&tethered&together.&
Figure&11-36
The&communication&between&to&neurons&occurs&at&the&synapse.&It&converts&a&chemical&
signal&into&an&electrical& signal.&The&presynaptic&nerve&terminal&comes&into&close&
proximity&to&the&postsynaptic&nerve&cell.&
The&presynaptic&nerve&terminal&contains&neurotransmitter&molecules&inside&synaptic&
vesicles.&An&AP&in&the&presynaptic&nerve&terminal&will&cause&the&release&of&
neurotransmitters&into&the&synaptic&cleft.&
The&neurotransmitter&may&bind&to&receptors&or&open&ligand-gated&channels.&This&will&&
alter&the&membrane&potential&of&the&postsynaptic&terminal.&
Figure&11-37
Figure&11-38
Ach&receptor/channel&is&a&pentameric&protein&complex.&
Comprised&of&2&alpha,&1&beta,&1&delta&and&1&gamma&subunit.&The&neurotransmitter&Ach&
binds&to&each&of&the&alpha&subunits.
When&Ach&binds&to&each&of&the&alpha&subunits,&it&causes&a&conformational&change&un&
the&transmembrane&alpha&helices.&This&leads&to&the&opening&of&the&channel&gate.&
Figure&11-34
The&patch&clamp&technique&allows&scientists&to&measure&the&activity&of&a&single&ion&
channel&in&a&living&cell&in&real&time.&
Chapter(11
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