Membrane Transport and Disease Flashcards
Simple diffusion
Small gases, water, lipophilic molecules
No transporters and no specificity
Facilitated diffusion
Specificity
Requires transporter
Saturation kinetics observed
No direct Energy
Ligate gated channels respond
Signaling molecule
Open channels respond to
Local concnetrations of solutes
Voltage-gated channels respond to
Membrane potential changes
Channels responding to covalent modification typically
Phosphorylation
Mechanosensitive channels respond to
Deformations in bilayer
Aquaporins role, location, regulation
Water translocation
Differnet tissues
Exo/endocytosis
Aquaporins exampel of
Mechano-sensitive channel
Aquaporin sturcture
Alpha-helical homotetramers…hourglass shape
NDI
Nephrogenic Diabetes insipidus
Most common form of NDI
Defect in vasopressin receptor making kidney tubules unresponsive to vasopression (X-dominant)
Other form of NDA
Defect in aquaporin-2 for water reabsorption (recessive)
Symptoms of NDI
Large urine output, dehyration
F class pump
H+ across inner mitochondrial membrane
V class pump
H+ across endosomal/lysosomal mebrnae
P class pump
H+, Na+, K+, Ca2+ across plasma membrane
ABC class pumps
Found in plasma and intracellular membrnaes…catalyze influx of lipids, peptides, ions, and drugs
Primary carriers
ATp or GTP driven
Secondary carriers
Concentration driven
Importance of nuclear pore membrane wrapping
Transport of membrane proteins back into nucleus from the ER
Effective channel size of nuclear pore
9-26 nm
Fast diffuson of nuclear pore
<5 kDa
Slow diffusion of nuclear pore
6-50 kDa
Active transport of nuclear pore
> 50 kDa
NLS
Signal for import…string of basic amino acids (+ charged)
NES
Hydrophobic amino acids
NRS
Tell to stay in the nucleus
Nuclear recycling mechanism
Binding of calcineurium marks NES of NF-AT and activates import signal via dephosphorylation…once back inside the nucleus, calcineurium leaves, NF-AT rephosphorylated, and NES exposed
What causes calcineurium to bind to NF-AT outside fo cell
High Calcium concentration
Small G proteins activated and inactivated by
Activated by GEF (guanine-nucleotide-exchange-factor)
Inactivated by GAP (GTPase-activating-protein)
GEF reaction
Removes GDP from Ras and replaces with GTP
Movement of ____ drives active nuclear transport
Ran - small G-protein
Ran-GTP/Ran-GDP locations
Ran-GTP - nucleus
Ran-GDP - cytosol
Ran-GAP
Ran GTPase-activating protein…dephosphorylates the Ran-GTP complex in cytosol
Ran-GEF
Ran gunaine nucleotide exchange factor (bound to chromatin)
Phosphorylates RAN-GDP in the nucleus
Importin steps
Importin binds cargo protein with NLS
Complex associates with fibrils and enters nucleus
RanGTP binds importin inside nucleus and displaces cargo
Importin and Ran-GTP exit nucleus
Ran Binding Protein displaces RanGTP and importin is free
RanGAP activates RanGTP and hydrolyses GTP
RanGDP recycles to nucleus where RanGEF promotes exchange of GDP for GTP
Export steps
Exportin binds target AND RanGTP Complex moves out Ran binding protein displaces RanGTp Exportin releases cargo RanGTP released from RanBP RanGAP activates RanGTP and hydrolyses Exportin and RanGDP back to nucleus RanGDP converted by to RanGTP by RanGEF
ALS Very early symptoms
Fatigue, muscle weakness, poor concentration
ALS early
Cramps, spasticity, limb onset, slurred or nasal speech, bulbar onset
ALS late
Difficulty moving, dysphagia, dysarthia
ALS terminal
Resp failure or penumonia
Only small % of ALS is ____
inherited
Only ALS therapy and what it does
Riluzole
Blocks voltage gated sodium channels to prevent glutamate release
Most common mutation of ALS
C9orf72 (GGGGCC) hexanucleotide expansion
ALS mutations of C9orf72
Haploinsufficiency due to reduced expression of gene copy on expanded repeat halotype
RNA gain-of-function toxicity because of aggregates formed
Abnormal bidirectional transcription of expanded repeat sequences followed by Non-AUG-initiated tranlation into aggregation prone proteins
3 things the GGGGCC mutation does
1) Directly clog NPC
2) Bind to RanGAP preventing nuclear import
3) Abnormal form of tranlation to form toxic dipeptide rpeeat proteins (DPRs) that interphere with import through karyopherins
