GIRIJA MAGANTIM.PHARM

(PHARMACOLOGY)

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.

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.

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

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.

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

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.

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.

Alzheimers & parkinson:profound loss of nicotinic receptors in cortical layers

schizophrenia:mental disorder mainly associated with brain dopaminergic hypothesis

Autism:disorder of neuraldevelopmentImpaired social interaction and verbal

and non verbal communication.

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.

Nicotine Receptors in the Brain.mp4

RECEPTOR-TYPE LOCATION EFFECTNICOTINIC AGONIST

NICOTINIC ANTAGONIST

Muscle-type:(α1)2β1δε[24]

or(α1)2β1δγ

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:(α3)2(β4)3

autonomic gangliaEPSP, 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:(α4)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:(α3)2(β4)3 Brain

Post- and presynaptic excitation

•nicotine•epibatidine•acetylcholine•cytisine

•hexamethonium•mecamylamine•tubocurarine•Dextromethorphan

Homomeric CNS-type:(α7)5

Brain

Post- and presynaptic excitation,[24] mainly by increased Ca2+ permeability

•epibatidine•dimethylphenylpiperazinium

•varenicline [26]

•mecamylamine•memantine•amantadine•α-bungarotoxin[1]

•Dextromethorphan