Receptors 2
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Transcript of Receptors 2
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Dr Manjuprasad
Moderator: Dr Vijayalaxmi M.K
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They are the molecules which relay signals
from receptors on cell surface to target
molecules inside the cytoplasm or nucleus.
Discovered by Earl Wilbur Sutherland in 1971
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Types:
• Hydrophobic: eg; DAG, phosphotidyl inositol
• Hydrophilic: eg; cAMP, cGMP, IP3 & calcium
• Gases : eg; NO, CO, H2S
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Synthesized, released & broken down again
in specific reactions by enzymes.
Can be stored & quickly released when
needed
Production, release and destruction can be
localised
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Cyclic nucleotides: cAMP
cGMP
Calcium
Lipid derivatives: IP3
DAG
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cAMP Synthesized from ATP
Regulates some ion channels as ligands
Regulates kinase
which phosphorylates substrates
- increases glycogen breakdown
- decrease glycogen synthesis
-increase cardiac beat strength
Eg: Adrenaline, Glucagon, LH
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cGMP Made from GTP
Membrane bound or soluble
Can act as a receptor
Regulates some ion channels and protein kinases
Important in smooth muscle relaxation and visual
system
Eg: ANP, NO
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Calcium:
At rest maintains low cytoplasmic
concentration
Channels open with ligand gated or voltage
gateing
Actions: muscle contraction
neuronal transmission
cellular motility
cell growth
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Inositol tri-phosphate
Hydrophilic
Agonist for internal calcium channel
[Ca++]i rises
Multiple effects through Ca++-binding
proteins
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Diacylglycerol
Hydrophobic
Targets PKC (a kinase)
PKC requires Ca++ and DAG
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Types:
• Voltage gated
eg: Lignocaine, verapamil
• Ligand gated
eg: gabapentine, nicotine
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Multiple isoforms
Generation of action potential
Sodium channels
One α and 2β
α subunit has 4 domains- sodium ion
selective pore forming pseudo tetramer
Β subunit span the membrane once
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Each domain has 6 membrane spanning helices (S1-S6)
Extracellular loop S5 & S6 or pore forming loop dips back into the pore
Provides selective filter for sodium ions
S4 of each domain surrounding the pore contain charged amino acids that forms the voltage sensor
Cause conformational change in pore at more positive voltage leading to opening of pore
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Calcium channel
This has a large α subunit (4 domains & 6
membrane spanning helices),
3 regulatory subunits ie β,δ and γ
Types:
L-Type- long lasting
found in Skeletal muscle, smooth muscle, bone,
cardiac myosites and dendrites
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P-type (purkinje)
Purkinje neurons in the cerebellum / Cerebellar
granule cells
N-type (neuronal)
Throughout the brain and peripheral nervous system
R-type (residual)
Cerebellar granule cells, other neurons
T-type (transient)
neurons, cells that have pacemaker activity, bone
(osteocytes)
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Potassium channels:
form channels as tetramers
4 membrane spanning domains
2 pore domain or leak potassium channels
-Dimers having 4 membrane spanning domains
surrounding 2 P loops
-Voltage insensitive
-Regulated by G proteins and H ions
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• Activated by binding of ligand to a specific site
which causes conformational change in the
channel
• Specialized ion channels that are activated by
intracellular small molecules
Belong to Kv family
Eg:-cyclic nucleotide gated channel
-IP3 sensitive Ca channels
-5HT3 regulated channels
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Large proteins consisting of a single chain upto
1000 residues with single membrane spanning
helix
Important role in-cell division
-growth
-differentiation
-inflammation
-tissue repair
-apoptosis
-immune response
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Receptor tyrosine kinases
Serine/ threonine kinases
Cytokine receptors
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Insulin, EGF, PDGF, NGF, FGF, VEGF
Have a single polypeptide chain except for insulin
receptor
Extracellular cysteine rich residues, short
transmembrane domain and intracellularly
containing one tyrosine kinase domains
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lack intrinsic enzyme activity. When
occupied, they associate with, and activate,
a cytosolic tyrosine kinase, such as Jak (the
Janus kinase)
for these receptors include cytokines such as
interferons and colony-stimulating factors
involved in immunological responses.
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Ligand binding -- dimerises
Phosphorylation of kinase domains
Activated receptor phosphorylates smad
Dissociation from receptor
Association with transcription factors and
gene regulation
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There are also inhibitory smads
Compete with phosphorylated smads to terminate
signalling
( S6 & S7 )
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Expressed in haematopoetic cells
Related to innate immunity
Structure is similar to kinase linked receptors
Ligands- peptidoglycans, lipopolysaccharides,
and viruses
Activation produces an inflammatory response
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These are ligand activated transcription
factors that transduce signals by modifying a
gene transcription
Present in soluble phase become mobile in
presence of ligand and translocate from
cytoplasm to nucleus
RXR dwell mainly in nuclear compartment
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Type 1:Receptors of steroid harmones
Eg: estrogen, progesterone, testosterone
Type 2:ligands present in cytoplasm to some
extent
Eg: PPAR-that recognises fatty acids
Type 3: characteristics of both 1 & 2
Imp role in endocrine signalling
Eg: thyroid harmone receptor, VitD receptor
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Myasthenia Gravis
Testicular feminization syndrome
Cystic Fibrosis
SIDS
Lambert eaton syndrome
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Goodman and Gilman – 12th edition
Rang and Dales pharmacology 7th edition
Textbook of medical pharmacology – Padmaja
udaykumar
Uptodate.com
Second messenger and signal transduction-
Dr Tim Bloom