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 There are two types of acetylcholine receptors
– muscarinic and Nicotinic receptors. Although the same neurotransmitter binds
to both, their mechanism of action is different. While Nicotinic receptors are
channel proteins that allow the flow of ions when Acetylcholine binds to it,
Muscarinic receptors change shape and trigger a pathway in the target cell; that
is-phosphorylating various second messangers.

receptors are found in skeletal muscle cells at neuromuscular junctions while
Muscarinic receptors exist in the CNS , heart muscle, smooth muscle or the
parasympathetic nervous system.

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The mechanism
of muscarinic receptors are as follows; When Acetylcholine binds to a
muscarinic receptor, it undergoes a conformational change and a G protein is
activated. There are 2 classes of these G- proteins; monometric and heterometric. The latter class is made up of alpha,
beta and gamma subunits. The beta and gamma subunits can form a stable dimer
called ‘beta – gamma complex’

The alpha subunit is bound to beta-gamma dimer and GDP ( the inactive
state of G proteins). After Ach binds to the muscarinic receptors and they are
activated, the receptor catalyses the exchange of GTP for GDP (guanosine
diphosphate and guanosine triphosphate) and the
beta-gamma complex dissociates from the alpha subunit. Thus, muscarinic
receptors undergo a conformational change and activates multiple molecules of G

The activated alpha subunit activates phospholipase C- an enzyme that
produces inositol 1,4,5-trisphosphate (IP3)
and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (a lipid
which is a component of the lipid bilayer) .The IP3 causes calcium
ions to be released from the endoplasmic reticulum. The endothelium releases various vasoactive
factors and which can be vasodilatory or vasoconstrictive; one of the
vasodilatory factors is Nitric oxide causes vasodilation of smooth muscles.


NO is formed
from nitric oxide synthase (NOS) enzyme; this enzyme converts the amino acid L-
Arginine to NO. The endothelial NOS (eNOS) is the particular isoform that
produces the nitric oxide in the vascular system. The inactive endothelial NOS is
attached to caveolin- a protein that’s located in infoldings called calveolae in
the cell membranes. An increase in calcium ion level inside the cell cause the separation
of calveolin and the eNOS and as a result the enzyme is activated. The increase
in the intracellular calcium ion level is as a result of depletion of calcium
stores in the endoplasmic reticulum due to the series of reactions caused by acetylcholine
binding to muscarinic receptors. The depletion of these calcium stores cause
calcium ion channels on the cell membrane to open hence allowing flow of extracellular
calcium ions into the cell. The calcium ions attach to calmodulin- a protein
located in the cytoplasm of cells. The finding causes structural changes to the
calmodulin which enable it to bind to eNOS. Endothelial NOS thus converts the
L-arginine in calmodulin to Nitric oxide. NO diffuses to the smooth muscle where
it binds to guanylyl cyclase (sGC).
This causes the enzyme to be activated. The active enzyme increases the rate at
which GTP is converted to cyclic guanosine monophosphate (cGMP). cGMP
causes asodilation by reducing muscle tension.




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