receptors
TRANSCRIPT
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By Dr Manjuprasad M.S
Moderator: Dr Vijayalaxmi MK
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Definition
Theories
Types
GPCRs
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The component of a cell or organism that
interacts with an agonist and initiates the
chain of events leading to agonist observed
effects.
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Occupation theory:
The interaction between the 2 molecules ie drug
and receptor to be governed by law of mass
action and the effect to be a direct function of
drug receptor complex
D+R DR E
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Intensity of response is proportional to the
fraction of receptors occupied by the drug and
maximal response occurs when all receptors are
occupied
Drugs exert All or none phenomenon
A drug and receptor have a complementary
structural features like lock and key
this theory just gave a fundamental concept
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Rate theory
Magnitude of response depends upon rate of
agonist/ receptor association and
dissociation.
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GPCR`s
Ligand gated ion channels/ionotropic
receptor
Kinase linked receptors
Nuclear receptors
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It was discovered by Alfred G.Gilman and
Martin Rodbel for which they won nobel prize
in physiology in 1994.
There are about more than 1000 known
GPCRs
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GPCRs are divided into three distinct families.
There is considerable sequence homology
between the members of one family, but none
between different families.
All have same seven-helix structure, but differ in
other respects, principally in the length of the
extracellular N terminus and the location of the
agonist binding domain.
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Group I,
the largest group, contains the receptors for
catecholamines, peptide hormones,
neuropeptides, and glycoproteins.
Group II, contains
the secretin/glucagon/vasoactive intestinal
peptide receptor family.
Group III
contains the metabotropic receptors (eg,
calcium-sensing and glutamate receptors)
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G-protein-coupled receptors consist of a single
polypeptide chain of up to 1100 residues .
comprises seven transmembrane α-helices, with
an extracellular N-terminal domain of varying
length, and an intracellular C-terminal domain.
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The helices are connected by 3 loops, both
intra and extracellularly.
3rd cytoplasmic loop couples to G-protein.
(heterotrimeric GTP binding proteins)
In synthesis of GPCR, during mRNA splicing,
additions/deletions/substitution of bases
lead to variation in specificity of receptor.
Leads to functional selectivity.
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2 Types
Heterotrimeric referred to as large G
proteins that are activated by GPCRs and are
made up of α,γ and β.
Small G proteins or monomeric belong to Ras
superfamily of small GTPases
involved in signal transduction.
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Associated with guanine nucleotides – GTP
and GDP.
α subunit interacts with GTP/GDP and also
has enzymatic action.
Remain as a complex due to addition of
hydrophobic groups
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Gαs , Gαolf : activates plasma membrane adenylyl
cyclases, increasing cAMP, which stimulates
phosphorylation of target proteins
Gαs and its downstream signaling can be covalently
activated by cholera toxin
.
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Gαi , Gαo : inhibit most adenylyl cyclases,
decreasing cellular cAMP.
Gαi and Gαo can be covalently inactivated and
their signaling turned off by Pertussis toxin.
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Gαq , Gα11 : activate phospholipase Cβ
Gα12 , Gα13 : enhance Rho kinase and change
expression of some genes
Gα transducin: activates cGMP phosphodiesterase
that cleaves and depletes cytoplasmic cGMP
(retina only)
Gα gustducin:activates cAMP phosphodiesterase
that cleaves and depletes cAMP (taste receptors)
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Adenylyl cyclase
Phospholipase C
Ion channels
Rho A/Rho Kinase
MAP Kinase
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Forskolin and fluoride ions can directly
activate cAMP
PDEs like theophylline, Rolipram, milrinone
can act indirectly by decreasing cAMP
degradation.
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Ex: vasopressin on liver cells.
Muscarinic and α adrenoceptor agonists
acting on smooth muscle and salivary glands.
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Can directly act on ion channels , without 2nd
messengers.
Especially influence K+ and Ca+ channels.ex:
m2 AChR in cardiac muscle – enhance K+
permeability.
Inhibitory drugs like opioids .
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Couples to G12-13 subtype
Free Gα interacts with guanosine nucleotide
exchange factor, facilitates GTP-GDP
exchange in Rho kinase.
Rho kinase involved in Pulmonary HTN.
Fasudil- under trials for use in Rx of
Pulmonary HTN.
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Involved in cell division,
apoptosis, and tissue regeneration.
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Phosphorylation
Receptor agonist complex internalization
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Four types of protease-activated receptors
(PARs), have been identified.
Eg.Thrombin activate PARs by snipping off
the end of the extracellular N-terminal tail
of the receptor to expose five or six N-
terminal residues that bind to receptor
domains in the extracellular loops
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It is thought to play a role in inflammatory
pain.
A PAR molecule can be activated only once,
because the cleavage cannot be reversed
Inactivation occurs by a further proteolytic
cleavage, or by desensitisation, involving
phosphorylation.
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Calcium sensing receptor: autosomal
dominant hypocalcemia
CXCR 4 : target of HIV
Endothelin receptor B(Etb) : hirschsprung’s
disease
Rhodopsin: in Retinitis pigmentosa.
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BIBLIOGRAPHY
Goodman and Gilman – 12th edition
Introduction to Physiology- Guyton – 11th edition
Essentials of medical pharmacology – K.D.Tripathi
Rang and Dales pharmacology 7th edition
Textbook of medical pharmacology – Padmaja
udaykumar
Basic clinical pharmacology Katzung 11th edition
Uptodate.com
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