Nicotinic receptors

1. GIRIJA MAGANTI
M.PHARM
(PHARMACOLOGY)

3. Forty years ago, the binding
of α-bungarotoxin was used
to discover the muscle
type nicotinic receptors in
electric rays (Torpedo
californica).
Functional and structural
information was also found
by studying the
homologous acetylcholine
binding protein found in
Lymnaea stagnalis.

4. It is a ligand-gated
channel
Composed of five subunits
arranged to create a
central channel though
the cellular membrane
The subunits are selected
from pool of 16
homologous polypeptides
(α1-9,β1-4,γ,δ,ε) are the
subunits from which
various nicotinic receptors
are formed.Homomeric in
CNS and heteromeric in
muscle are seen.

7. NM RECEPTORS
Neuromuscular junction
(depolarizing of muscle end
plate)contraction of
skeletal muscle
Opening of
cataion(Na+,k+)channel
Agonist:PTMA,nicotine.
Antagonist:tubocurarine,
α-bungarotoxin,
NN RECEPTORS
Autonomicganglia:depolar
ization
Adrenalmedulla:catechola
-mine release
CNS:excitation or inhibition.
Opening of
cataion(Na+,k+,ca+)
DMPP,nicotine
Hexamethonium,
trimethonium

8. Binds
acetylcholine, it
is a natural
ligand
It needs two ach
molecules for its
activation
Forms a central
channel through
the cellular
membrane and
allows for the
passage of
cations through
the membrane.

9. In the closed state the ion channel is
occluded by a ‘hydrophobic girdle’ that
constitutes a barrier to ion permeation.
 Agonist binding in the extracellular
domain promotes a conformational change
that results in a rotational movement of the
M2 helices lining the pore. Twisting
of the girdle widens the pore by ~3 Å,
sufficient for ion permeation.
Each subunit consists of
4transmembrane segments, the second
transmembrane segment (M2) lines the ion
channel.
 The extracellular N-terminal domain
of every subunit contains a ‘cys-loop’ that
is the characterstic of LGIC

11. It is also the target of numerous natural
and manmade toxins, including venom
and nerve gases.
 Prolonged nicotine exposure causes an
upregulation in high-affinity receptors
and densensitization.
Defects in receptor are also suspected in
several disorders, including schizophrenia,
Parkinson’s , Alzheimers ,myasthenia
gravis and ADNFL epilepsy.

13. Myastheniagravis:auto
immune disorder due to
development of antibodies
directed to nicotinic
receptors at the endplate
causing structural damage
to NMJ
Cause muscle weakness
due to repeated firing.

14. Alzheimers & parkinson:profound loss
of nicotinic receptors in cortical layers
schizophrenia:mental disorder mainly
associated with brain dopaminergic
hypothesis
Autism:disorder of neuraldevelopment
Impaired social interaction and verbal
and non verbal communication.

15. ADNFL EPILEPSY:AUTOSOMAL DOMINANT
NOCTURNAL FRONTAL LOBE EPILEPSY

 A missense mutation in nicotinic
receptor α4 subunit is associated with
this ADNFL epilepsy.
Characterized by frequent ,violent,brief
seizures at night in childhood.

16. Nicotine Receptors in the Brain.mp4

17. RECEPTOR-TYPE LOCATION EFFECT
NICOTINIC
AGONIST
NICOTINIC
ANTAGONIST
Muscle-type:
(α
1)
2β
1δε
[24]
or
(α
1)
2β
1δγ
Neuromuscular junction
EPSP, mainly by
increased Na
+
and K
+

permeability
•acetylcholine
[1]
•carbachol
•suxamethonium
•α-bungarotoxin
[25]
•α-conotoxin
•tubocurarine
[1]
•pancuronium
•atracurium*
Ganglion-type:
(α
3)
2(β
4)
3
autonomic ganglia
EPSP, mainly by
increased Na
+
and K
+

permeability
•acetylcholine
[1]
•carbachol
•nicotine
[1]
•epibatidine
•dimethylphenylpiperazinium
•mecamylamine
[1][25]
•trimetaphan
•hexamethonium
•bupropion
•ibogaine
•18-methoxycoronaridine
•Dextromethorphan
Heteromeric CNS-
type:
(α
4)2(β2)3
Brain
Post- and
presynaptic excitation
,
[24]
mainly by
increased Na
+
and K
+

permeability
•nicotine
•epibatidine
•acetylcholine
•cytisine
•varenicline
•mecamylamine
•methylcaconitine
•α-conotoxin
•Dextromethorphan
Further CNS-type:
(α
3)2(β4)3 Brain
Post- and
presynaptic excitation
•nicotine
•epibatidine
•acetylcholine
•cytisine
•hexamethonium
•mecamylamine
•tubocurarine
•Dextromethorphan
Homomeric CNS-
type:
(α
7)5
Brain
Post- and
presynaptic excitation
,
[24]
mainly by
increased Ca
2+

permeability
•epibatidine
•dimethylphenylpiperazinium
•varenicline
[26]
•mecamylamine
•memantine
•amantadine
•α-bungarotoxin
[1]
•Dextromethorphan