Drug-Receptor bonding & signal transduction

Dr V.N NDIKUM
8-Mar-12

Characteristics of a Receptors

Specificity

Receptor interacts with one type of ligand or a structurally related family of

ligands Competition between related ligands

Affinity

Example: glucose transporter binds D-glucose specifically

Intrinsic activity Saturability

Energetics of ligand receptor interactions Energetics of binding determine specificity A measure of the ability of a bound drug to activate the receptor Distinguishes agonist from antagonist Finite number of binding sites on a receptor, along with specificity of

interactions, implies that binding sites can become fully occupied with ligand molecules Additionalligand leads to non-specific binding

Molecular Level of Drug-receptor interaction Specificity of Molecular Level Recognition :

Protein receptors have specific three dimensional

structure Generally, receptor binding sites are regions of the protein with a specific arrangement of charged amino acid side chains that are exposed, allowing access to the binding molecule (drug) Site must be spatially and energetically favorable for binding Binding of ligand to receptor can lead to conformational changes making further binding more favorable

Types of Chemical Bonds in LigandReceptor Interactions

Affinity and Specificity based on chemical bonds
Covalent binding Ionic bonds (initial attraction) Cation- interactions, hydrogen bonds Vander Waals forces, hydrophobic

interactions

Types of Bonding between & Receptors

Types of receptors

Types of receptors

10

>50 % of all prescribed drug affects GPCRs

11

Signal transduction

1. enzyme linked
(multiple actions)

2.

ion channel linked

(speedy)

3. G protein linked
(amplifier)

4. nuclear (gene) linked

(long lasting)

12

Signal transduction 1. G protein-linked receptors

Structure: Single polypeptide chain threaded back and forth resulting in 7 transmembrane helices Theres a G protein attached to the cytoplasmic side of the membrane (functions as a switch).

13

14

Signal transduction

2.

Tyrosine-kinase receptors
Structure: Receptors exist as individual polypeptides Each has an extracellular signal-binding site An intracellular tail with a number of tyrosines and a single helix spanning the membrane

15

16

Signal transduction
3. Ion channel receptors
Structure:
Protein pores in the plasma membrane

17

18

Signal transduction: Intracellular receptors Not all signal receptors are located on the

plasma membrane. Some are proteins located in the cytoplasm or nucleus of target cells. The signal molecule must be able to pass through plasma membrane. Examples:
Nitric oxide (NO) Steroid
(e.g., estradiol, progesterone, testosterone) and thyroid hormones of animals).
19

Concept of second in molecular Signal transduction

The concept of Second messenger

Second Messenger
20

Characteristics of Second Messengers

Small, nonprotein, water-soluble

molecules or ions Readily spread throughout the cell by diffusion Two most widely used second messengers are:
1. Cycle AMP 2. Calcium ions Ca2+

21

Adenylate Cyclase, cAMP, Protein Kinase A (PKA)

As R1
Gs

Ai
Adenylate Cyclase

R2
Gi

GTP

GTP ATP-Mg++

GDP
AMP PDE

GDP

cAMP
Protein

C Reg C Reg

C C

Protein Kinase A (PKA)

PDE - phosphodiesterase

PKA
Protein-P

22

cAMP Second Messenger System

Katzung, Basic and Clinical Pharmacology, 2001, p. 124

23

Phospholipase C, Inositol Trisphosphate (IP3), Ca2+ and Diacylglycerol, Protein Kinase C (PKC) Ca++
A

R
Gq

PLC DAG PIP2

PKC
Protein

IP3 Ca++
PLC phospholipase C PIP2 phosphatidylinositol bisphosphate IP3 inositol trisphosphate

Protein-P

Endoplasmic Reticulum

DAG diacylglycerol PKC protein kinase C 24

Guanylate Cyclase, Nitric Oxide Synthase (NOS), cGMP,

cGMP-dependent Protein Kinase (PKG) and Phosphodiesterase

Intracellular Ca++ Stores

Ca++
Ca++

C.M.

Ca++

Membrane Bound Guanylate Cyclase

NO

GTP
Soluble Guanylate Cyclase

NO Synthetase

+ Citrulline GTP

NO

cGMP
Arginine

PDE

GMP

Ion Channels cGMP-Dependent PK PDEase Activity

25

Second messengers
Calcium Ions (Ca2+) and Inositol Trisphosphate
Calcium more widely used than cAMP used in neurotransmitters, growth factors,

some hormones Increases in Ca2+ causes many possible responses such as:
Muscle cell contraction Secretion of certain substance Cell division

26

Benefits of a signal-transduction
Two benefits of a signal-transduction pathway
1. Signal amplification 2. Signal specificity

Signal amplification
Proteins persist in active form long enough

to process numerous molecules of substrate Each catalytic step activates more products than in the proceeding steps
27

28

Functional classification of receptors

29

System acetylcholinergic

Type acetylcholine nicotinic receptors acetylcholine muscarinic receptors

monoaminergic 1-adrenoceptors 2-adrenoceptors -adrenoceptors dopamine receptors serotonin receptor

aminoacidergic

GABA receptors
glutamate ionotropic receptors glutamate metabotropic receptors

glycine receptors
histamine receptors peptidergic purinergic opioid receptors other peptide receptors adenosine receptors (P1 purinoceptors) P2 purinoceptors

Subtypes of Norepinephrine Receptors

RECEPTORS 1-adrenoceptors Subtype 1A 1B 1D 2-adrenoceptors 2A 2B 2C 2D -adrenoceptors 1 2 Gq/11 Gq/11 Gq/11 Gi/o Gi/o Gi/o Gi/o Gs Gs Transducer IP3/DAG IP3/DAG IP3/DAG cAMP cAMP cAMP cAMP cAMP cAMP Structure (aa/TM) 466/7 519/7 572/7 450/7 450/7 461/7 450/7 477/7 413/7

Gs, Gi/o cAMP

408/7

Subtypes of Dopamine Receptors

RECEPTORS
dopamine

Subtype
D1 D2 Gs Gi Gq/11 Gi Gi Gs

Transducer
cAMP cAMP IP3/DAG, K+, Ca2+ cAMP cAMP, K+ cAMP

Structure (aa/TM)
446/7 443/7

D3 D4 D5

400/7 386/7 477/7

Subtypes of Serotonin Receptors

RECEPTORS 5-HT
(5-hydroxytryptamine)

Subtype 5-HT1A Gi/o

Transducer cAMP

Structure 421/7

5-HT1B
5-HT1D 5-ht1E 5-ht1F

Gi/o
Gi/o Gi/o Gi/o

cAMP
cAMP cAMP cAMP

390/7
377/7 365/7 366/7

5-HT2A
5-HT2B 5-HT2C 5-HT3 5-HT4 5-ht5A 5-ht5B

Gq/11
Gq/11 Gq/11 Gs ? ?

IP3/DAG
IP3/DAG IP3/DAG cAMP

471/7
481/7 458/7 387/7 357/7 370/7

internal cationic channel 478

5-ht6
5-HT7

Gs
Gs

cAMP
cAMP

440/7
445/7