Solute carrier proteins

7 January 2017 1Dept of Plant Biotechnology

ROLE OF SOLUTE
CARRIER PROTEINS
UPASANA MOHAPATRA
Jr.MSc PLANT
BIOTECHNOLOGY
PALB 6290
UAS,GKVK,Bengaluru
7 January 2017 Dept of Plant Biotechnology 2

CONTENTS
1. CELL MEMBRANE
2. TRNASPORT THROUGH CELL MEMBRANE
3. TRANSPORT PROTEINS
4. DIFFERENCE BETWEEN TRANSPORT AND CARRIER
PROTEINS
5. SLC PROTEINS AND ITS REQUIREMENTS
6. MODE OF WORKING OF SLC PROTEINS
7. NOMENCLATURE AND CLASSIFICATION OF SLC
PROTEINS
8. SLC PROTEINS AND DISORDERS
9. ROLE OF SLC PROTEINS
10. TRANSPORTERS AS TARGET OF DRUGS(CASE STUDY)

CELL MEMBRANE
Structure of cell
membrane
Lipid Bilayer -2
layers of
phospholipids (Gorter
& Grendel (1925)
a. Phosphate head is
polar (water loving)
b.Fatty acid tails non-
polar (water fearing)
c. Proteins embedded
in membrane
Phospholipid
Lipid Bilayer

Polar heads
love water &
dissolve. Fluid Mosaic
Model of the
cell
membrane
Proteins in
membrane
Polar heads
love water &
dissolve.
Non-polar tails
hide from
water.

Transport
Carrier
Mediated
Active
Primary Secondary
Facilitated
Non Carrier
Mediated
Passive

TRANSPORT MECHANISMS
TRANSPORT
Passive processActive process
Primary Transport
Secondary Transport
Simple diffusion
Facilitated diffusion
Osmosis
Bulk flow
Filtration
Require
energy
Don’t require
energy

1. DIFFUSION
• Diffusion is the net movement of
molecules (or ions) from a region of
their high concentration to a region
of their lower concentration.
• The molecules move down a
concentration gradient.
• Molecules have kinetic energy,
which makes them move about
randomly.
• As a result of diffusion molecules
reach an equilibrium where they are
evenly spread out.
This is when there is no net
movement of molecules from either
side.

Molecules That Diffuse Through Cell
Membranes
1. Oxygen – Non-polar
so diffuses very
quickly.
2. Carbon dioxide –
Polar but very small
so diffuses quickly.
3. Water – Polar but
also very small so
diffuses quickly.

2. Facilitated Diffusion
 Movement of molecules is
still PASSIVE just like
ordinary diffusion, the only
difference is, the molecules
go through a protein channel
instead of passing between
the phospholipids.

Molecules will randomly move
through the opening like pore, by
diffusion. This requires no energy,
it is a PASSIVE process.
Molecules move from an area of
high concentration to an area of
low conc.

3. Osmosis
‘The diffusion of water from an
area of high concentration of water
molecules (high water potential) to
an area of low concentration of
water (low water potential) across a
semi permeable membrane.’
Isotonic solution-solution with the same solute concentration as that of the
cytosol
Hypotonic solution -lower concentration of non permeating solutes than that
of the cytosol (high water concentration),cells absorb water, swell and may burst
(lyse)
Hypertonic solution -has higher concentration of nonpermeating solutes than
that of the cytosol (low water concentration)cells lose water.

4. VESICULAR TRANSPORT
It is the transport of membrane bounded substances
moving across plasma membrane
It is classified into:
1. Exocytosis 2. Endocytosis.

Endocytosis
A. It is a process by which the large number of particles are taken
with forming the vesicle into the cell
B. It is classified into:
1. Phagocytosis-
It is a process by which the large number of particles are
engulfed into the cell.
2. Pinocytosis
It is a process by which the large number of particles which
are soluble in water are taken into the cell

5. Active transport
A. Active transport is the transport
of substances from a region of
lower concentration to higher
concentration using energy,
usually in the form of ATP.
B. Examples: Na, K and Ca active
transport.
• 1.Sodium-potassium pump
• 2.Calcium pump
• 3.Potassium hydrogen pump

Active Transport needed
for,
1.Maintaining the Chemical
and Electrical Charge at
rest.
2.Intake of Substances
through gated Channels.
3.Collecting of ions with
more concentration.

NEED OF ACTIVE TRANSPORT
1. Cells cannot rely solely
on passive movement of
substances across their
membranes.
2. In many instances, it is
necessary to move
substances against their
electrical or chemical
gradient to maintain the
appropriate
concentrations inside of
the cell or organelle.

PRIMARY ACTIVE TRANSPORT
1. Primary active transport is the
transport of sustances uphill
using energy (ATP hydrolysis)
2. It cause a conformational
change that results in the
transport of the molecule
through the protein.
3. Eg. Na+-K+ pump.

In this energy stored in the
electrochemical gradient of an ion is
used to drive the transport of another
solute against a concentration or
electrochemical gradient. The ion
moving down its electrochemical
gradient is referred to as the driving
ion because it is movement of this ion
that drives the uphill movement of
another ion/molecule (driven
ion/molecule).
May be
1) Antiport
2) Symport
Secondary active transport or
Co-transport

Transport Proteins
1. A transport protein (variously referred to as a transmembrane
pump, transporter protein, escort protein, acid transport
protein, cation transport protein, or anion transport protein) is
a protein that serves the function of moving other materials
like ions, small molecules, or macromolecules, such as another
protein, across a biological membrane within an organism.
2. Transport proteins are integral transmembrane proteins; that is
they exist permanently within and span the membrane across
which they transport substances.

Difference between transport proteins
and carrier proteins.
1. The proteins may assist in the movement of
substances by facilitated diffusion or active
transport.
2. The two main types of proteins involved in
such transport are broadly categorized as
either channels or carriers
3. Transport proteins and the carrier proteins are
not same as carrier protein is a type of
transport protein.

Difference Between Carrier And
Channel Proteins
Carriers
1. A carrier is not open
simultaneously to both the
extracellular and
intracellular environments.
Either its inner gate is
open, or outer gate is open.
2. Carriers have binding sites.
3. But only 100 to 1000
molecules typically pass
through a carrier molecule
in the same time.
Channels
1. A channel can be open to
both environments at the
same time, allowing the
solutes it transports to diffuse
without interruption.
2. But pores and channels do
not.
3. When a channel is opened,
millions of ions can pass
through the membrane per
second.

SLC PROTEINS AND ITS
REQUIREMENTS
1. SLC proteins are the solute carrier proteins that transport the
solutes across the membrane.
2. Lipid bilayers are highly impermeable to
most polar molecules.
3. To transport small water-soluble molecules into or out of cells
or intracellular membrane-enclosed compartments, cell
membranes contain various membrane transport proteins, each
of which is responsible for transferring a particular solute or
class of solutes across the membrane. these are known as
solute carrier proteins.

SLC PROTEINS AND ITS
REQUIREMENTS
These are required because
1) Some molecules(including charged, uncharged polar
molecule) can not pass through the phospholipid bilayer of
membrane which is impermeable to them.
2) Some molecules also move against the direction of
concentration gradient.
3) The liquid inside and outside the cell have different
substances. Sometimes cell has to work and use some energy
to maintain proper balance of ions and molecules..

HYDROPHOBIC
MOLECULES
SMALL
UNCHARGED
POLAR
MOLECULES
LARGE
UNCHARGED
POLAR
MOLECULES
IONS
CO2, O2
ETHANOL
GLUCOSE
H
+
,
HCO3
-
Ca2+ , Mg2+
MOVEMENT ACROSS LIPID BILAYER

Mode Of Working Of Slc Proteins Or
Types Of Solute Movement
SOLUTE MOVEMENT
ACTIVE TRANSPORT PASSIVE TRNSPORT
PRIMARY
ACTIVE
TRANSPORT
SECONDARY
ACTIVE
TRANSPORT
SIMPLE
DIFFUSION
FACILLATED
DIFFUSION
OSMOSIS

Mechanism Of Facilitated Diffusion
• To pass through a lipid bilayer, a polar or charged solute must
first give up its interactions with the water molecules in its
hydration shell, then diffuse through a solvent (lipid) in which
it is poorly soluble
• The energy used to strip away the hydration shell and to move
the polar compound from water into and through lipid is
regained as the compound leaves the membrane on the other
side and is rehydrated.
• The intermediate stage of transmembrane passage is a high-
energy state comparable to the transition state in an enzyme-
catalyzed chemical reaction.

Mechanism Of Facilitated Diffusion
• An activation barrier must be overcome to reach the
intermediate stage . The energy of activation (G‡) for
translocation of a polar solute across the bilayer is so
large that pure lipid bilayers are virtually
impermeable to polar and charged species over
periods of time.
• Membrane proteins lower the activation energy for
transport of polar compounds and ions by providing
an alternative path through the bilayer for specific
solutes.

(a) In
simple diffusion, removal of the
hydration shell is highly
endergonic,and the energy of
activation (G‡) for diffusion
through the bilayer is very high.
(b) A transporter protein reduces
the G‡ for transmembrane
diffusion of the solute. It does
this by forming noncovalent
interactions with the dehydrated
solute to replace the hydrogen
bonding with water and by
providing a hydrophilic
transmembrane passageway.
7 January 2017 31Dept of Plant BiotechnologyPrinciples of biochemistry Lehinnger

Mechanism of primary active transport
(P-type Na-K ATPase)
1. In virtually every animal cell type, the concentration of Na is
lower in the cell than in the surrounding medium, and the
concentration of K is higher.
2. This imbalance is maintained by a primary active transport
system in the plasma membrane. The enzyme Na-K ATPase,
discovered by Jens Skou in 1957, couples breakdown of ATP
to the simultaneous movement of both Na and K against their
electrochemical gradients.
3. ATPase cycles between two forms, a phosphorylated form
(designated P-EnzII) with high affinity for K and low affinity
for Na, and a dephosphorylated form (EnzI) with high affinity
for Na and low affinity for K ion.

•Because three Na ions move
outward for every two K ions
that move inward, the process
is electrogenic—it creates a net
separation of charge across the
membrane.
•The result is a transmembrane
potential of 50 to 70 mV
(inside negative relative to
outside), which is characteristic
of most animal cells and
essential to the conduction of
action potentials in neurons.7 January 2017 33Dept of Plant Biotechnology

MOVEMENT ACROSS TONOPLAST IN PLANT
CELL
Plant Physiology 5th EditionTeiz And Zeiger

CLASSIFICATION OF SLC PROTEINS
AND NOMENCLATURE
Molecular Aspects of Medicine 34 (2013) 95–107

NOMENCLATURE OF SLC PROTEINS
1. The SLC gene nomenclature system was originally
established in the 1990s by Matthias Hediger in
collaboration with Phyllis McAlpine, the first chair of the
HGNC.
2. In general, the genes are named using the root symbol
SLC, followed by a numeral (e.g., SLC1, solute carrier
family 1), followed by a letter which defines the subfamily
(only A is used when the family has not been subdivided)
and finally a number designating the individual transporter
gene (e.g., SLC3A1).
3. Transporters are assigned to a specific family if the
encoded protein has at least 20% amino acid sequence
identity to other members of that family

Classification Of Solute Carrier Proteins

SLC PROTEINS AND DISORDERS
SLC SERIES FUNCTION DISORDERS
Glutamate
transport
(SLC1 family)
play a critical role in the central
nervous system by maintaining
extracellular glutamate
concentrations below
excitotoxic levels
Amyotrophic Lateral Sclerosis (ALS)
as well as Alzheimer disease (AD).
Urate transport
(SLC2 family)
SLC2A9 initially considered a
glucose or fructose transporter,
is now established as a urate
transporter
Genetic defects of SLC2A9 are linked
to early-onset nephropathy
Neuro
transmitter
transport
(SLC6 family)
transport substrates such as
serotonin, dopamine,
norepinephrine,
GABA, taurine, creatine, as well
as amino acids
Mood disorders such as depression,
addiction, aggression, post-traumatic
stress disorder (PTSD), anxiety,
obsessive compulsive disorder (OCD),
and disorders such as attention deficit
hyperactivity disorder (ADHD)
Di- and tri-
carboxylate/sulf
ate transport
(SLC13 family)
Na+-coupled di- and tri-
carboxylate/sulfate transporter
Pathogenesis of the two
Inborn metabolic diseases glutaric
aciduria type 1 (GA1) and Canavan
disease (CD).7 January 2017 40Dept of Plant Biotechnology

SLC PROTEINS AND DISORDERS
SLC SERIES FUNCTION DISORDERS
Organic anion
transport
(SLC17 family)
organic anion
transporters
Gout, and possibly schizophrenia, as well as
amyotrophic lateral sclerosis (ALS), Alzheimer disease,
and Huntington disease (VGLUTs).
Mitochondrial
transporter
(SLC25 family)
muscle pain, progressive hypertrophic cardiomyopathy
(severe anemia with hypochromia, microcytosis and
ringed sideroblasts in the bone marrow).
Anion
transporters
(SLC26 family)
anion
transporters and
channels,
oxalate urolithiasis, gastric hypochlorhydria, distal renal
tubular acidosis, and male
infertility.
Zinc transport
(SLC30 and
SLC39
families)
zinc
transporters
Abnormal zinc metabolism has also been shown to be
associated with the risk of
diabetes, breast cancer and prostate cancer
Riboflavin
transport
(SLC52 family)
Multiple acyl-CoA dehydrogenase deficiency (MADD),
Brown-Vialetto-Van Laere Syndrome, a rare autosomal
recessive neurologic disorder characterized by
sensorineural hearing loss and a variety of cranial nerve
palsies7 January 2017 41Dept of Plant Biotechnology

Role Of Transporters Or SLC Proteins
In Other Prospects
1. Transporters can serve as drug targets or as a mechanism to facilitate drug
delivery to cells and tissues. Recently exploited drug transporter targets
include neurotransmitter transporters (SLC6 family),intestinal bile acid
transporters (SLC10 family) and cation-Cl cotransporters (SLC12 family).
2. Dapaglifloxin (Forxiga), the first of a class of inhibitors of the SGLT2
(SLC5A2) sugar transporters, has been approved in Europe for treatment
of Type 2 diabetes.
3. The intestinal oligopeptide transporter PepT1 (SLC15A1) or transporters
at the blood–brain barrier (various SLC families) are proving to be
important drug delivery systems.

SLC Transporters As Therapeutic Targets:
Emerging Opportunities
Objective
1. The role of SLC transporters in human health
and discuss how defects in SLC transporters
cause disorders.
2. Methodologies that may be used to develop
drugs to treat diseases associated with genetic
variants of SLC transporters.
Lawrence Lin et al.,
Nature 2015

Types Of Mutations In SLC Transporter Genes

The Transporters As Target Of Drugs
Sl no. Transporter family Used for
1 SLC12 transporters as targets of
diuretic drugs
used to treat hypertension and heart
failure
2 SLC6 transporters as
neuropsychiatric drug targets
Drugs for treating depression
3 Glucose transporter inhibitors to decrease blood glucose level.
4 Uric acid transporter inhibitors for Gout
5 Glycine transporter inhibitors.- for schizophrenia
6 Bile acid transporter inhibitors – for lowering blood cholesterol level
and prevnting cardiovascular
diseases.
7 Nutrient transporter inhibitors. –. for prevention of tumor cell growth
in cancer

CONCLUSION
1. As protein structures become ever more available, improved
strategies emerge using this information, along with
improvements in rational drug discovery approaches, to
facilitate development of both new drugs as well as research
tools to more deeply understand the biological roles of
transporters.
2. The future challenge for the scientific community will be the
biochemical, biophysical, physiological and
pharmacological assessment of all these novel gene products
in a manner that can be used to improve our understanding
of transporter biology, with a focus on human physiology,
pathophysiology and drug discovery.

REFERENCES
1. The Abcs Of Membrane Transporters In Health And
Disease(slc Series): Introduction Matthias A et al.,.
Mol Aspects Med. 2013 Apr; 34(2-3): 95–107.
2. SLC Transporters As Therapeutic Targets: Emerging
Opportunities Lawrence Lin1,et al., Nat Rev Drug
Discov. 2015 Aug; 14(8): 543–560.
3. Principles Of Biochemistry Lehinnger 5th Edition
4. Plant Physiology Fifth Edition Lincoln Teiz And
Eduardo Zeiger

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