Acetylcholine intracellular action

Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl -A (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft (see text). This step can he blocked by botulinum toxin. Acetylcholine s action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosome-associated proteins VAMPs, vesicle-associated membrane proteins.

Each muscle fiber is innervated by a branch of an alpha motor neuron. The synapse between the somatic motor neuron and the muscle fiber is referred to as the neuromuscular junction. Action potentials in the motor neuron cause release of the neurotransmitter acetylcholine. Binding of acetylcholine to its receptors on the muscle fiber causes an increase in the permeability to Na+ and K+ ions. The ensuing depolarization generates an action potential that travels along the surface of the muscle fiber in either direction that is referred to as a propagated action potential. This action potential elicits the intracellular events that lead to muscle contraction. 

At the neuromuscular junction, the terminus of the axon is separated from the sarcolemma by a cleft about 4 nm wide. When an action potential arrives at the terminus, it activates a voltage-sensitive Ca " ion channel. This results in Ca + ions diffusing into the terminus increasing the intracellular Ca + ion concentration, which stimulates exo-cytosis of acetylcholine from the terminus into the cleft. The acetylcholine diffuses across the cleft and binds to receptors on the motor end-plate (Figure 13.12) on the muscle side of the cleft. The binding of acetylcholine to... 

Release of acetylcholine When an action potential propagated by the action of voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels in the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and release of acetylcholine into the synapse. This release is blocked by botulinum toxin. By contrast, black widow spider venom causes all of the cellular acetylcholine stored in synaptic vesicles to spill into the synaptic gap. 

In GH cells SST inhibits prolactin secretion induced by cAMP analogs and K+-induced depolarization in addition to inhibiting adenylyl cyclase activity [192], Similar data were also obtained with ACTH-secreting AtT-20 cells [203]. PTX blocks SST inhibition of ligand-induced and cAMP analog-induced secretions in both GH and AtT-20 cells [106,107]. Thus, it is clear that a G protein is involved in both the cAMP dependent and the cAMP-independent actions of SST. Quin-2 measurements showed that exposure of cells to SST lowers the intracellular Ca2+ levels. This effect is also PTX-sensitive [211-213], The decline in intracellular Ca2+ was concluded to be secondary to SST hyperpolarizing the cells by increasing K+ conductance [214,215]. Acetylcholine, like SST, causes inhibition of adenylyl cyclase, hy-... 

Atropine is the classic anticholinergic bronchodila-tor. It antagonizes acetylcholine, resulting in reduced intracellular cyclic guanosine monophosphate (cGMP) and smooth muscle relaxation. In horses, the therapeutic index of atropine is narrow and the duration of action is short (0.5-2.0 h). Adverse systemic effects associated with parenteral atropine administration include mydriasis, ileus, dry mucous membranes, blurred vision, excitement and tachycardia. Atropine is not suitable for routine administration to horses with recurrent airway obstruction. 

The ensuing discussion will deal with that major category of receptors that are essentially components of cellular membranes. For example, the acetylcholine receptor involving skeletal muscles exerts its effect at the end of the motor nerve and its junction with the muscle (neuromuscular junction, see Chapter 7) by a depolarizing action. The fact that receptors are embedded in muscle cell membranes can be surmised by the fact that the contractile effect can be initiated by simply applying acetylcholine to the surface of the muscle preparation intracellular injection of the agonist produces no effect. A more interesting... 

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