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Lecture 67: Bulk Transport (Physiology), Types of Pinocytosis, Exocyst…
Lecture 67: Bulk Transport (Physiology)
MAJOR TYPE 1
ENDOCYTOSIS
:explode:
1)
Phagocytosis
:recycle:
2)
Pinocytosis
:red_flag:
2A)
Receptor-Mediated Endocytosis
:warning:
constitutive (
always
occurring)
induced (receptor-mediated)
Clathrin-mediated endocytosis
:warning:
Caveolin-Coated Vesicle-mediated Endocytosis
:warning:
Non-clathrin/non-caveolin-mediated endocytosis
:forbidden:
coat protein(s)-if any- & mechanism is UNKNOWN!
Viruses using pathway:
-
Rotavirus
-Influenza virus
-Lymphocytic choriomeningitis virus
distinct
membrane lipid & protein composition (cholesterol & sphingolipid-rich)
form
signaling membrane subdomains
dynamin-2-dependent
(pinching off similar to clathrin-coated vesicles)
regulated by src Family Kinases
MULTIPLE TYPES!
Caveolin 1,2, 3
Caveolin 1 & 2
(expressed by
most
cells)
Caveolin 3= Unique!
:!:
-only expressed in skeletal/smooth mm., glial cells, early post-natal peripheral nn.
Pathologies
Viruses
using caveolin-coated vesicle entry pathway
SV40 virus
papillomarvirus
diseases assoc. w/Caveolin 3 mutations
limb girdle musc. dystrophy
rippling muscle disease
distal myopathy
hyperCKemia
MANY viruses use this pathway for mammalian cell entry!
Examples
-
Hepatitic C virus
-
Dengue virus
-
Reovirus
Energy- DEPENDENT!
Constitutive internalization of coated vesicles from plasma membrane
ligand binding to cell surface receptor
accelerates
int. rate
Coat proteins
"coat" cytoplasmic membrane surface
Types
-clathrin
-caveolin
-others
Basal internalization rate VARIES by cell type!
Macrophages
internalize
~3%
of membrane SA/minute
Fibroblasts
~1%
/minute
accelerated by GF/hormone binding
Total plasma membrane SA NOT changed, so equivalent amounts of plasma membrane are being internalized & replaced
LDL Receptor Recycling & Disease
:fire:
Specific plasma membrane
LDL (low-density lipoprotein)
receptors
LDL receptors w/bound LDL cluster in
clathrin
-coated pits
LDL interalized more SLOWLY in the
absence
of LDL receptors
receptors w/
bound LDL
internalized
FASTER
(than those without)
LDL internalization downregulate cholesterol synthesis
:!:
Hypercholesterolemia
:!!:
caused by:
-LDL receptor deficiency
-LDL receptor mutation inhibiting localization to clathrin-coated pits
Notice:
xanthomas
arise from deposition of plasma LDL-derived cholesterol into macrophages of skin
cell drinking
constitutive (
always
occurring)
internalize extracellular fluid
2B)
MACROPINOCYTOSIS
("large cell drinking")
:champagne:
large membrane ruffles fold over to engulf fluid & contents
Actin cytoskeleton involved
blocked by
P21-activated kinase-1
(regulates actin dynamics & block/inhibits actin polymerization!)
Pinosomes fuse w/
early
endosomal compt.
Some viruses use this to enter cell!
vaccinia virus
HIV1
Echovirus type 1
Adenovirus 3
cell eating
Receptor-mediated
Induced process (initiated by ligand binding to receptors on phagocytic cells)
internalize
large
particles
-bacteria
-dead or damaged cells
-asbestos fibers, glass beads, etc.
CLINICAL RELEVANCE :star:
(Phagocytosis)
early line of
defense
against bacteria!
Some bacteria have
protection mechanisms
that allow to
escape
degradation
through phagocytosis!
Salmonella enterica
(food poisoning)
secretes protein that
blocks fusion
of phagosome w/lysosomes -> blocks degradation!
Mycobacteria
(TB)
blocks uncoating
of coat proteins that's requires for lysosomal fusion!
NO degradation
of phagocytosed bacteria
live in
protected
intracellular
vesicular environment
Energy-
dependent
Vesicles <250 nm diameter
Mammalian phagocytic cells
macrophages
dendritic cells
neutrophils
Actin cytoskeleton required for internalization!
Phagosomes
fuse
w/lysosomes to degrade contents/kill bacteria!
Live animal cells
"do not eat me!" signals
membrane proteins that bind to
inhibitory
receptors on phagocytic cells
coated vesicles- proteins coating intracellular surface of endocytosing vesicles
MAJOR TYPE 2
EXOCYTOSIS
:black_flag:
SNAREs
:black_flag:
Soluble NSF (NEM-Sensitive Factor) Activating Protein Receptor Protein
at least 39 different SNAREs identified!
2 Basic Types
:!!:
1) v-SNARE
vesicle-SNARE
2) t-SNARE
target-SNARE
different v/t-SNARE combo's impact specificity of vesicle fusion events!
mediate vesicle fusion
Ca2+ dependent self-assembly
forms conducting channels spanning
2 lipid bilayers
-> brings them VERY CLOSE together!
Tethering vs. Fusion
:black_flag:
Tethering Vesicles
to target membrane mediated by "tethers" (
Rab effector proteins
)- small G-protein :!:
Homotypic Tethering
2 intracellular vesicles fuse!
Heterotypic Tethering
fusion of 1 intracellular vesicle + plasma membrane
Fusion
of
exocytic vesicle
w/plasma membrane (
mediated
by
SNAREs
)
Regulation
:black_flag:
(Examples)
Secretion of Growth factor(s) like NT's from neurons
Insertion of membrane transporters (regulate transport activity)
Possible Disease Connections
:black_flag: :!!:
1) Synaptic Exocytosis Defects
:checkered_flag:
may play role in multiple neurodegenerative diseases
2) Type 2 Diabetes
:checkered_flag:
some types assoc. w/diminished depolarization-induced insulin exocytosis
3) Cystic Fibrosis (CF)
:checkered_flag:
some CFTR mutations impede movement by vesicles from ER -> plasma membrane
energy-
dependent
! (
ATP
)
"priming" of membrane site for vesicle fusion to occur
exocyst complex
secures secretory vesicle to plasma membrane
Types of Processes!
:!!:
Constitutive
continuous
Ca2+ dependent!
Regulated
respond to signal (ligand binding to membrane receptor, ex: NT release)
Ca2+ dependent!
MAJOR TYPE 3
TRANSCYTOSIS
:red_flag:
Endocytosis of fluid & solutes along with receptor-bound ligands from 1 solution (apical or basolateral)
movement
within
vesicles through cell
exocytosis of vesicle contents at
other
membrane surface
COMBO
of
endo
cytosis (1 side) and
EXO
(other side)!
Examples:
-Endothelia & capillaries
-Intestinal epithelia
-Lung
-Thyroid
-BBB
Types of Pinocytosis
Exocyst complex
Tethering
v-SNARE/t-SNARE
Fusion! :star:
