L3 - Transporters Flashcards
define passive diffusion
movement of molecules from region of high concentration to low concentration across a membrane
what type of molecules can passively diffuse? give examples
small
uncharged
non polar
lipid soluble
O2, CO2, glycerol, ethanol
fucntion of transmembrane proteins
form transporters or ion channels that allow movement of large / polar molecules across membrane
function of ion channels
act like a pore to allow passive diffusion of specific ions through the membrane
define facilitated diffusion
passive diffusion of molecules facilitated by a protein eg ion channel
define primary active transport
using a carrier protein (transporter) and energy provided from conversion of ATP to ADP +Pi (via ATPase) to transport a molecule across a membrane against its conc gradient
example of primary active transporter
Na / K / ATPase pump
define secondary active transport
uses energy from the flow of ions down a concentration gradient to co-transport another molecule against its conc gradient across a membrane
what are the two types of secondary active transport
symport (cotransport) -> molecule transported in same direction as ion providing the energy
antiport -> molecule transported in opposite direction to ion providing the energy
list the 3 functional types of transporter
- transporters that maintain ion gradients (ion transporters and pumps)
- nutrient / metabolite transporters
- NT transporters
why is NT re-uptake from the synaptic cleft important?
- prevent new unwanted AP generation
- synapse would become refractory/inactivated due to receptor desensitisation if NT wasnt removed
how are NT removed from cleft
- passive diffusion into surrounding neurones
- degradation by enymes
- reuptake into terminal or astrocytes
what are the two types of plasma membrane transporter superfamilies
- Na+ / Cl- dependant transporters
2. Na+ /K+ dependant transporters
how many TMDs do the Na+ / Cl- dependant transporters have
12
are the N and C terimnals of the Na+ / Cl- dependant transporter intra/extra cellular?
both intracellular
describe structure of Na+ / Cl- dependant transporter superfamily
→ 12 transmembrane (H.phobic) domains
→ intracellular N & C terminal
→ extracellular loop between TMD 3&4 which contains 2-4 glycosylation sites
give examples of transporters that are Na+ / Cl- dependant
SERT NET DAT GABA transporter Glycine transporter choline transporter
list the types of glutamate transporters
EAAT 1-5
where is EAAT1 EAAT2 EAAT3 EAAT4 EAAT5 found
EAAT1 -> glial cells
EAAT2 -> glial and neuronal cells
EAAT3 &4 -> neuronal cells
EAAT5 -> retina
how many TMDs do the Na+/K+ dependant transporters have
6-10 Hphobic
example of a Na+/K+ dependant transporter
EAAT (glutamate and aspartate transporter)
what is an electroneutral transporter and give an example
a transporter that doesnt change the electrochemical portetial of a cell (moves same number of + / - in and out)
SERT
what is an electrogenic transporter and give an example
a transporter that changed the electrochemical potential of a cell (moves an odd number of + / - in or out of the cell)
glutamate EAAT
where else is EAAT3 expressed other than glutamate neurones and why
GABAergic neurones as glutamate is the precursor for GABA
why is glutamate re-uptake into glial cells more energy efficient?
requires less energy because there is a smaller concentration gradient of Glutamate in the glial cell compared to the nerve terminal
due to conversion of glutamate to glutamine in glial cells
describe the glutamate - glutamine shuttle process
- glutamate taken into glial cell by EATT1/2 where its converted to glutamine by glutamine synthase
- glutamine leaves glial cell via N amino acid transporter
- glutamine transported into neurone by A amino acid transporter
- glutaminase converts glutamine back into glutamate in the nerve terminal
- glutamate packaged into vesicle
what ion is used to co transport in the A and N amino acid transprters?
Na
describe calcium independant NT release
reverse transport -> when transporters work in reverse and move NT into the cleft rather than into nerve terminal
what enzymes convert
glutamate -> glutamine
glutamine -> glutamate
glutamine synthase
glutaminase
what GABA transporters are found on the membranes of astrocytes
GAT-2
GAT-3
what is believed to cause reverse transport of NTs?
the Na gradient that usually co-transports the NT in.
if intracellular Na gets too high it may move in the opposite direction into the cleft (via the transporter) taking NT with it
what does packaging NT into vesicles prevent
- leakage into cleft
- NT metabolism in the terminal
- toxicity to neurone
name the monoamine ACh GABA/Glycine Glutamate transporters
VMAT (1&2)
VAchT
VIAAT (vesicular inhibitory amino acid transporter)
V-glut 1, 2, 3
what does VMAT transport
serotonin
dopamine
NA
histamine
what does VMAT transport
serotonin
dopamine
NA
histamine
where is
VMAT1
VMAT2 expressed
endocrine cells
neurones
what is a difference between the vesicular and plasma membrane glutamate transporters?
the membrane transporter transports aspartate and glutamate, the vesicular can only transport glutamate
describe structure of the VMAT and VAchT transporters
- 12 TMDs
- large Hphilic loop with 3-5 potential glycosylation sites between TMD 1&2 (in vesicle lumen)
- N and C terminal is in cytoplasm of nerve terminal
describe structure of VIAAT
- 10 TMDs
- Long N terminal and short C terminal, both in cytoplasm of nerve terminal
- large loop between TMD 1&2 (inside vesicle)
describe significance of glutamate transporters in epilepsy
- knockout mice for the equivalent EAAT2 transporter experienced seizures
name the GABA plasma membrane transporter
GAT
describe the mechanism of anti-epileptic drug tiagibine
- it is a GABA transporter blocker - prevents re-uptake of GABA into nerve terminal
- increases [GABA] in cleft and so increases receptor binding
- increased inhibition
list diseases that can be treated by interfering with transporters (and which transporters)
- Epilepsy -> GAT blockers
- ADHD -> DAT blockers
- Depression -> NA / 5-HT (NET / SERT) blockers
describe the mechanism of action of fenfluramine (anti-obesity drug) in regards to the serotonin transporter
causes SERT to work in reverse, depositing 5-HT into the cleft instead of re-uptaking it (reverse transport)
also disrupts vesicle storage
wwhat effect will blocking VMAT and other vesicle transporters have?
reduce [NT] in the cleft, as less can be exocytosed
describe significance of reverse transport in ischemia
reverse tsport of plasma membrane glutamate transporters occurs in ischemia, which results in increased [glutamate] in cleft causing excitotoxicty
where does cocaine act?
SERT, DAT, NET
inhibiting reuptake
where does amphetamine act?
DAT, SERT, NET clocking reuptake
also causes DAT reverse transport
where does MDMA act?
SERT, where it blocks reuptake and promotes reverse transport
MDMA has higher affinity for SERT than serotonin itself
