MEMBRANE TRANDP Flashcards
Pores
- PhoE
- VDAC1
- perforin
- C9
- chironex fleckeri toxin (box jellyfish)
- AQP1 - CHIP28
- AQP2
PhoE
- from E.Coli
- trimer of identical Beta barrel monomers
- 0.7 * 1.1 nm pore
- tricon-like end
VDAC1
- voltage dependant anion channel
FUNCTIONS
Main gate for metabolites through MOM - ATP/ADP & NAD+/NADH
- kreb cycle intermediates - cholesterol & glutamate
HK, GK and CK interact
- ATP source for enzyme activity
Controls flow of ions
- CL-, K+, Ca2+. Mg2+
ROS prefretial release
regulator for apoptosis
- under stimuli, VDAC1 undergoes oligomerization via Bax
- causes release of CYT c
regulated by actin and tubulin
perforin
- released by cytotoxic Tcells
- form 16 nm pore in target
Chironex fleckeri toxin (box jellyfish)
- porin
- K+ released from neurons
- hyperkalemia
- cardiac arrest
AQP1
- each monomer has a pore
- 6 TM spans
- amino & carboxyl ends are intracellular
- TM 2-3 and TM5-6 are loops B&E
*middle of these loops hace NPA motif
*TWO NPA motifs come together in folding - teramer
- protons not transported
WATER SELECTIVITY DEPEND ON:
- positive charged Arg-195 residue - prevents cation flux
- pore diameter of 2.8Å
- near channel midpoint, two positivlty charged dipoles disrupt hydorgen bond break proton wire
AQP2
- KIDNEY
- vasopressin induced water permeability
- triggers fusion of AQP2-bearing vesicles to apical PM of collecting duct principal cells
- increased water permeability allowing water to be reabsorbed from urine
Mechanism
- ADH binds receptor
- G protein alpha subunit activated AD
- cAMP increase
- PKA activated
- phosphorylated AQP2-bearing vesicles
- allows dynien to bind
- iniates exocytosis
MUTATIONS
ND1
- large urine volume
- mutation in V2 vasopressin receptor
OR
- mutation to APQ2 structure leading to retention in ER
Carriers (facilitated
- SLC2
GLUT1 -
GLUT4 - insulin
GLUT1
SLC2A1 gene
- 12 TM
- 7,8,11 - amphipathic helcies surround putative ‘conduit’
- glucose transporter
- passive process
- found in BRAIN & kidneys
IMPAIRMENT
- impaired glucose transport espcially the brain
- microcephaly (small head) - mental and motor developmental delays
- siezures within 4 months
- ketogenic diet
- body no longer need to transport glucose because it can be synthesised from ketones in the tissue
- can supply adequate fuel levels
GLUT4
regulated by insulin
- insulin stimulates translocation of GLUT4 to PM
- IRS-1 binds to activated RTK
- P85 & P110 associate
- P110 catalyses PIP2 -> PIP3
- resuts in PDK & Atk interaction
AS160 activated and catalyses Rab10 GDP->GTP
- triggers exocytosis of GSV to PM
- Implemenation of GLUT 4 into PM
Carriers (Active transport primary)
P-type ATPases
- ‘Na+,K+ATPases’, Ca2+ ATPases, ‘H+,K+ ATPases’, Metal ion pumps (DMT1), Flippases (P1-5)
V-type ATPases
- vesicular H+ ATPases
F-type ATPases
- mitochondrial ATPsynthase
- connection to bacteriorhodsin
ABC transporters
- ABCB1- floppase
- P-glycoprotein
Na+,K+ATPases
- carrier and enzyme
- maintains excitability for excitability
- 1/3 of cells energy
Structure
- hererodimeric : alpha&beta subunits
- beta subunit requited for proper assembly
- alternative isoforms: alpha1-4, beta1-3
inhibitors
- ‘cardiac glycosides’ - digitoxin
- treat heart failure
- increase NA conc
decrease NA/CA exchangers NCX1
CYCLE OF PUMP
Binding of Sodium (Na⁺)
ATP Binding
Phosphorylation and Conformational Change
Release of Sodium (Na⁺)
Binding of Potassium (K⁺)
Dephosphorylation
Conformational Change to E1
Release of Potassium (K⁺)
Ca2+ ATPases
SERCA
- key in regulation of cytoplasmic Ca2+
maintain low conc in cell
often active after muscle or nerve excitation
H+,K+ ATPases
- proton pump for stomach
site for treatment of - dyspepsia, peptic ulcer disease, gastroesophageal reflux disease
PPIs - omeprasole
cf rantidine histamine h2 rece
vesicular H+ ATPases
- roles of acidificaiton
lysosomes
piump across PM
allowes for uprake of iron
Mitochondrial ATPsynthase
Structure: Consist of two subunits: F₀ (membrane-bound proton channel) and F₁ (ATP-synthesizing catalytic domain).
Mechanism: Protons flow through F₀, driving rotation that powers ATP synthesis in F₁.
Location: Found in the mitochondrial inner membrane, chloroplast thylakoid membrane, and some bacterial membranes.
Energy Source: Utilizes proton motive force (PMF) to produce ATP from ADP and inorganic phosphate.
bacteriorhodopsin provies PMF by converting light into energy
Carriers (secondary)
COTRANSPORTERS
- SGLT - SLC5 - Na+-glucose transporter
- DMT1- H+/metal transporter
EXCHANGERS
- SLC4 - anion exchangers
AEI-3 - blocked by DIDs
AEI-1 - used in CO2 transport in blood
SGLT Na+-glucose transporter
- drives glucose up steep gradient
- 10,000 fold increase in SGLT1
GGM - defective trasport across intestinal brush barrier
- fatal in weeks
- glucose and galactose cannot be absorbed
- fructose is fine
lactose removed from diet - due to mutation in SGLT1
DMT1- H+/metal transporter
- 12 TMD
- glycosylated extracellular loop
- consensus transport mofitf on intracellilar loop
Type: Symporter that transports divalent metal ions (Fe²⁺, Zn²⁺, Mn²⁺, Cu²⁺).
Function: Responsible for the uptake of iron (Fe²⁺) into cells, particularly in the intestinal epithelium, and also transports other divalent metals like zinc, manganese, and copper.
Location: Primarily in the duodenum, kidneys, and other tissues.
Mechanism: DMT1 co-transports protons (H⁺) with divalent metal ions (e.g., Fe²⁺). This electrochemical gradient of protons, maintained by Na⁺/H⁺ exchangers, drives the symport of Fe²⁺ into the cell, ensuring efficient iron absorption.
Role: Crucial for iron absorption and maintaining iron homeostasis in the body.
Regulation: Expression is regulated by body iron levels. Low iron levels increase DMT1 expression to enhance iron uptake, while high iron levels reduce its expression.
Defects: Mutations in DMT1 can lead to iron deficiency anemia or disorders like hemochromatosis (iron overload).
AEI-3 - blocked by DIDs
AEI-1 - used in CO2 transport in blood
Type: Antiporter (exchanges bicarbonate (HCO₃⁻) and chloride (Cl⁻)).
Location: Plasma membrane of red blood cells and other tissues.
Function: Transports HCO₃⁻ out of the cell and Cl⁻ into the cell to maintain electrochemical balance.
Role: Important for CO₂ transport and pH regulation in red blood cells.
Inhibition: DIDS (4,4’-Diisothiocyanatostilbene-2,2’-disulfonic acid) is a known inhibitor of AEI, blocking the chloride-bicarbonate exchange, and thus impairing CO₂ transport and pH balance.
PATHOLOGIES
- Bartter syndrome
Cause: Mutations in genes encoding kidney transporters like NKCC2, ROMK, or CLCNKB.
Symptoms: Hypokalemia, hyponatremia, metabolic alkalosis, muscle weakness, growth retardation, polyuria.
Pathophysiology: Defective salt transport causes salt loss, leading to dehydration and electrolyte disturbances.
Treatment: Potassium supplements, salt supplements, potassium-sparing diuretics, and sometimes ACE inhibitors.
