Cholinergic neuron & Cholinergic Receptors

•Drugs affecting the autonomic nervous system(ANS) are divided into two groups according to the type of neuron involved in mechanism of action.

•The cholinergic drugs, which act on receptors activated by acetylcholine(Ach), Where as adrenergic drugs act on receptors stimulated by epinephrine or norepinephrine.

•The cholinergic drugs act by either stimulating or blocking the receptors of the ANS.

The cholinergic neuron

• The preganglionic fibres terminating in adrenal medulla.

• The postganglionic fibres of parasympathetic division use ACh as a neurotransmitter. The postganglionic sumpayhetic division of sweat glands also uses ACh.

• Ina ddition, cholinergicneurons innervate the muscles of somatic system and play an important role in CNS.

NEUROTRANSMISSION @ CHOLINERGIC NEURON:

• Neurotransmission at cholinergic neurons involves 6 sequential steps :

(1) Synthesis of ACh

(2) Storage of ACh

(3) Release of ACh

(4) Binding of ACh to the receptor

(5) Degradation of ACh in the syneptic cleft

(6) Recycling of Choline

(1) Synthesis of Acetylcholine :

• Choline js transported from extracellular fluid into the cytoplasm of cholinergic neuron by an energy dependent carrier system that co-transport the sodium and can be inhibited by the drug hemicholinium.

• Choline has quaternary nitrogen amd carries a permanant positive charge and thus cannot diffuse through the membrane.

• The uptake of choline is the rate limiting step in ACh synthesis.

• Choline acetyl tranferase catalyzes the reaction of choline with acetyle coenzyme A to form ACh ester in the cytosol.

(2) Storage of Acetylcholine in vessicle :

• ACh is packaged and stored in presynaptic vessicle by an active transport process.

• The mature vessicle contain not only acetylcholine but also ATP and proteoglycan.

• The vessicle contain primary neurotransmitter as well as cotransmitter (ATP) that increase or decrease the effect of the primary neurotransmitter.

(3) Release of Acetylcholine :

• When an action potential arrives at nerve ending, voltage gated calcium channels on the synaptic membrane open, causing an increase in concentration of intracellular Ca++.

• Eleveated Ca level promotes the fusion of synaptic vessicle with cell membrane and release of contents(ACh) into the synaptic space.

(4) Binding of Receptor :

• ACh released from synaptic vessicle diffuse across the synaptic space and binds to the post synaptic receptors of target cells.

• The post-synaptic cholinergic receptors on the surface of effector organs are divided into two classes; muscarinic and nicotinic.

• Binding to a receptor leads to the biological response within the cell. Such as initiation of nerve impulse in postganglionic fibre or activation of specific enzymes in effector cells, as mediated by 2ndry messenger mollecules.

(5) Degradation of Acetylcholine :

• The signal at the post-junctional effector site is rapidly terminated, beacause acetylcholinterase (AChE) cleaves ACh in to Chloine & acetate in the synaptic cleft.

(6) Recycling of Choline :

• Choline may be recaptured by a sodium coupled, high affinity uptake system that transport the mollecule back into the neuron. So that it can be available to be acetylated in to ACh.

Cholinergic Receptors (Cholinoreceptors)

• Two families of chiloceptors are muscarinic and nicotinic recptors, can be distinguished from each other on the basis of their different affinities for agents that mimics the action of ACh.

(1) Muscarinic Receptors

• Muscarinic receptors belongs to the class of G-protein-coupled-receptors( metabotropic receptors).

• These receptors in addition to binding ACh, also recognize muscarine, an alkaloid in certain poisonous mushroom.

• There are 5 types of muscarinic receptors (M1, M2,M3, M4, M5).

(i) Location of muscarinic receptors :

• These receptors are found on the autonomic effector organs such as heart, smooth muscles, brain and exocrine glands.

• M1 receptors are found on gastric parietal cells.

• M2 receptors are found on cardiac muscles & smooth muscles.

• M3 receptors are found on bladder, exocrine glands & smooth muscles.

==>•When muscarimic drugs given in high concentration then they may show some activity at nicotinic receptors also.

(ii) Mechanism of acteylcholine signal transduction:

• Signal can be generated by ACh by different mollecule mechanism on the receptor. For example :

• M1& M3 receptors are activated, the receptor undergoes a conformational change and interacts with a G-protein that activates Phopholipase C. This ultimately leads to production of 2ndry messenger IP3 and DAG.

• IP3 cause hyperpolarization by releasing of Calcium and DAG activates protein kinase C which phosphorylates many protein within the cell.

(iii) Muscarinic agonists :

• Pilocarpine is the non-selective muscarinic receptor used to treat xerostomia and glaucoma.

(2) Nicotinic Receptors :

• These Receptors in addition to binding with ACh, also recognise nicotine but show only a weak affinity for muscarine.

• The nicotinic receptors is composed of 5 subunits, & it function as ligand gated ion channel(ionotropic receptors).

• Nicotinic receptors are located in CNS, adrenal medulla, autonomic gangliaamd nueromuscular junction(NMj) in skeletel muscels.

• Binding of two ACh mollecules elicits a conformational change that allows the entry of sodium ions, resulting in depolarisation of the effector cells.

• Nicotine at low concomtration stimulates the receptor and at high concentration it blocks the receptor.

• Nicotinic receptors at NMj are differ from autonomic ganglia. For example : NMJ receptors are specifically blocked by atracurium and whereas ganglionic receptors are selectively blocked by mecamylamine.

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