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PURINERGIC RECEPTOR

PRESENTED BY

Sandhya Talla

M.PHARM (FIRST YEAR)

DEPARTMENT OF PHARMACOLOGY

CONTENT

• History & Introduction• ATP as neurotransmitter• Synthesis, store, release and metabolism of ATP• Types of purinergic receptor• Distribution of purinergic receptors• Structure of purinergic receptor• Purinergic signalling• Role of purinergic receptor• Therapeutic potential• Recent trends

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The transmitter substance release

from Non-cholinergic & Non-

adrenergic nerves of Gut may be

ATP or some related purine

nucleotide.

These nerves has been termed as

“Purinergic nerves”

Geoffrey Burnstock(1972)

(Molecular M.N.,2008)

HISTORY

(Ghosh,2008)

INTRODUCTION

What is purinergic receptors?

The purinergic system involves the purine nucleotides, ATP , ADP, and the

nucleoside, adenosine

Purinergic nerves are located on Aurbach’s plexus.

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Aurbach’s plexus is a collection of nerve fibre and that are mainly found in the muscle tissue of human intestine . These plexus are mainly responsible for generating peristalsis movement.

AURBACH’S PLEXUS:-

The substance must be released from terminal axon when nerves are activated.

ATP is contained in synaptic vesicles of both adrenergic and cholinergic

neurons, and it works as an energy currency.

ATP is released on nerve stimulation in a Ca2+-dependent fashion

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ATP as a Neurotransmitter ( burnstock,2006 )

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ATP

ADP

AMP

Adenosine

Inosine

ATpase

Adenosine deaminase

Adenosine uptake

P2 purinoreceptor

AdenosineLarge opaque vesicleContaining ATP

SMOOTH MUSCLE

Synthesis, storege, release and metabolism of ATP ( burnstock,2014)

.

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P1 P2

A1 A2 A3 P2X P2Y

Purinergic receptor

Types of Purinergic Receptors (Burnstock et al ,2012 )

P2Y1,P2Y2,P2Y4,P2Y6P2X1,P2X2,P2X3,P2X4

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Receptors Main distribution

A1 Brain, spinal cord,testis,heart.

A2 Brain, Heart,spleen, lungs.

A3 Lung,Liver, Brain, Testis.

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Receptors Main distribution

P2X1 Smooth muscle, cerebellum, platelets

P2X2 Smooth muscle, sensory, gangalia

P2X3 Sympathetic neuronsP2X4 CNS, testis,colon

Receptors Main distributionP2 Y1 Epithelial cell,Endothelial cell,

P2Y2 Immun cell, osteoblast,kidney tubules

P2Y4 Endothelial cell

P2Y6 Placenta,T cell,thymus

Distribution of purinergic receptors (Burnstock et al, 2012)

P1 receptor:- (G- protien couple receptors)

7-Transmembrane(TM) domains of

hydrophobic amino acid---constitute

an α-helix of ~21–28 amino acids

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Structure of Purine Receptor (Burnstock et.,al 2012)

P2x receptor :- ( Ligand gated ion channel)

Large extracellular loop, with 10 conserved

cysteine residues forming a series of disulfide

bridges.

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Structure of Purine Receptor

P2y receptor :-( G- protien couple receptor)

Some TM-spanning regions, particularly

TM3, TM6 & TM7 and structural diversity

of intracellular NH2 & COOH terminus

among P2Y sub-Types

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Structure of Purine Receptor

Short term neuronal signalling-

secretion

vasodilation

Co-transmission

Long term neuronal signalling

Cell proliferation

Cell differentiation

Inflammation

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Purinergic Signall ing (Burnstock,2014l)

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Co-transmission (Burnstock,2014)

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Cell proliferation and differentiation (Burnstock, 2014)

1) In Central Nervous System

2) In Respiratory System

3) In Cardiovascular System

4) In Gastrointestinal Tract

5) In endocrine system

6) In Urinary system

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Role of purinergic receptor

Release of excitatory neurotransmitter (GABA,glycine)

Release of inhibitory neurotransmitter (glutamate)

Anticonvulsant effects

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Central nervous System (Burnstock,2008)

Purine increases mucus secretion from goblets cells.

Purinergic activation causes bronchoconstriction.

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Respiratory system

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Cardiac system (Burnstock,2003)

Slows AV nodal conduction (negative dromotropy)

Decrease heart rate (negative chronotrophy)

Decrease atrial contractality (negative contraction)

Inhibits pacemaker

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It causes

Relaxation of stomach.

Decreases peristalsis movement.

P2x3 receptor present on gut wall produces pain sensation

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Gastrointestinal Tract

(Fernando, et al 2014)

Purinergic signaling causes contraction of urinary bladder.

Purinoceptor involved in regulation of renin secretion,

glomerular filtration and transport of water, ions, nutrients.

P2x3 responsible for micturation reflux and pain

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Urinary System

ATP stimulate release of insulin

ATP modulate aldosterone production

ATP inhibit secretion of estradiol and progesterone from ovary

Inhibit lipolysis

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Endocrine Glands

1) Parkinson’s disease :-

Adenosine A2a receptor antagonists are mainly used.

2) Epilepsy :-

Adenosine by activation of A1 receptors in hippocampus exerts

predominant inhibitory effects.

These inhibitory actions of adenosine can be used therapeutically

to suppress seizures.24

Therapeutic Potential

( Burnstock,et al 2003)

3) Ischaemia :-

Adenosine used as a cytoprotective agent during myocardial ischaemia

i) improved tissue perfusion

ii) anti-inflammatory action

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Therapeutic Potential

(Burnstock, et,al 2003)

Atherosclerosis:-

Adenosine and ATP have a number of cardiovascular protective effect in addition of vasodilation ,including promotion of the endothelial and smooth muscle cell proliferation and increased in the expression of vascular endothelial grawth factor (VEGF).

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Therapeutic Potential

(Burnstock,2003)

• Purinergic signalling in ovary

• Acupuncture : a Novel hypothesis for involvment of purinergic signalling

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Recent Trends

ATP produced inside the cell can be released into the extracellular area in different ways.

purinergic activity in ovary – including sensitivity of gonadotropin in several ovarian cells types, i.e Granulosa cell , theca cell.

role of ATP as an important intraovarian messenger and regulate the ovarian function.

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Purinergic signalling in ovary

(Molecular Reproduction and development,2015)

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Purinergic signalling in ovary

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Acupuncture: A novel hypothesis for the involvement of purinergic signalling

( Burnstock,2009)

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References

Molecular inervention ,M.N Ghosh; purinergic Nerves, 2004 M.N Ghosh purinergic receptors fundamental of experiments Annualreviews;structural and chemical organisation of Aurbach plexus. Geoffrey Burnstock (2006);Historical review: ATP as a neurotransmitter Geoffrey burnstock (2006 ); historical review : ATP as a neurotransmitter Geoffrey Burnstock (2012) purinergic signaling in healthy and diseased skin ;volume 132 Geoffrey Burnstock (2012);purinergic signaling in healthy and diseased skin Geoffrey Burnstock (2012);purinergic signaling in healthy and diseased skin Geoffrey Burnstock (2014);purinergic signaling;from discovery to current development Geoffrey Burnstock (2014);purinergic signaling ;from discovery to current development Geoffrey Burnstock (2008) ;purinergic signaling and disorder of CNS Geoffrey burnstock 2003;involvment of purinergic signaling in cardiovascular diseased fernando.ochoa-corts (2014) potential for developing purinergic drug for GIT disesead Geoffrey Burnstock;(2008) ;purinergic signaling and disorder of CNS Geoffrey Burnstock (2003); Involvment of purinergic signaling in cardiovascular diseased Angelica s (2015);purinergic signaling In overy molecular Reproduction and development Geoffrey Burnstock (2009)Acupuncture: A novel hypothesis for the involment purinergic signaling

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