Acetylcholinereceptors are of two kinds- Muscarinic receptors and Nicotinic receptors.
Although the same neurotransmitter binds to both, their mechanism of action isdifferent. While Nicotinic receptors are channel proteins that allow the flowof ions when Acetylcholine binds to it, Muscarinic receptors change shape andtrigger a pathway in the target cell; that is-phosphorylating various secondmessangers.Nicotinicreceptors are found in skeletal muscle cells at neuromuscular junctions whileMuscarinic receptors exist in the CNS , heart muscle, smooth muscle or theparasympathetic nervous system.The mechanismof muscarinic receptors are as follows; When Acetylcholine binds to amuscarinic receptor, it undergoes a conformational change and a G protein isactivated. 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 dimercalled ‘beta – gamma complex’The alpha subunit is bound to beta-gamma dimer and GDP ( the inactivestate of G proteins). After Ach binds to the muscarinic receptors and they areactivated, the receptor catalyses the exchange of GTP for GDP (guanosinediphosphate and guanosine triphosphate) and thebeta-gamma complex dissociates from the alpha subunit. Thus, muscarinicreceptors undergo a conformational change and activates multiple molecules of Gprotein. The activated alpha subunit activates phospholipase C- an enzyme thatproduces inositol 1,4,5-trisphosphate (IP3)and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (a lipidwhich is a component of the lipid bilayer) .
The IP3 causes calciumions to be released from the endoplasmic reticulum. The endothelium releases various vasoactivefactors and which can be vasodilatory or vasoconstrictive; one of thevasodilatory factors is Nitric oxide causes vasodilation of smooth muscles. NO is formedfrom nitric oxide synthase (NOS) enzyme; this enzyme converts the amino acid L-Arginine to NO. The endothelial NOS (eNOS) is the particular isoform thatproduces the nitric oxide in the vascular system.
The inactive endothelial NOS isattached to caveolin- a protein that’s located in infoldings called calveolae inthe cell membranes. An increase in calcium ion level inside the cell cause the separationof calveolin and the eNOS and as a result the enzyme is activated. The increasein the intracellular calcium ion level is as a result of depletion of calciumstores in the endoplasmic reticulum due to the series of reactions caused by acetylcholinebinding to muscarinic receptors. The depletion of these calcium stores causecalcium ion channels on the cell membrane to open hence allowing flow of extracellularcalcium ions into the cell. The calcium ions attach to calmodulin- a proteinlocated in the cytoplasm of cells.
The finding causes structural changes to thecalmodulin which enable it to bind to eNOS. Endothelial NOS thus converts theL-arginine in calmodulin to Nitric oxide. NO diffuses to the smooth muscle whereit binds to guanylyl cyclase (sGC).This causes the enzyme to be activated. The active enzyme increases the rate atwhich GTP is converted to cyclic guanosine monophosphate (cGMP).
cGMPcauses asodilation by reducing muscle tension.