Receptors

1. By Dr Manjuprasad M.S
Moderator: Dr Vijayalaxmi MK
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2.  Definition
 Theories
 Types
 GPCRs
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3.  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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4.  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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5.  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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6.  Rate theory
Magnitude of response depends upon rate of
agonist/ receptor association and
dissociation.
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7.  GPCR`s
 Ligand gated ion channels/ionotropic
receptor
 Kinase linked receptors
 Nuclear receptors
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8.  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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9.  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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10.  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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11. 11

12.  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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13.  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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14. 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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15.  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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16.  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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17.  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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18.  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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19. 19

20.  Adenylyl cyclase
 Phospholipase C
 Ion channels
 Rho A/Rho Kinase
 MAP Kinase
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21. 21

22.  Forskolin and fluoride ions can directly
activate cAMP
 PDEs like theophylline, Rolipram, milrinone
can act indirectly by decreasing cAMP
degradation.
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24.  Ex: vasopressin on liver cells.
 Muscarinic and α adrenoceptor agonists
acting on smooth muscle and salivary glands.
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25.  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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26.  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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27.  Involved in cell division,
apoptosis, and tissue regeneration.
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28.  Phosphorylation
 Receptor agonist complex internalization
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29. 29

30.  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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31. 31

32.  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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33.  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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34. 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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