Release Of Acetylcholine And Its Modulation By Toxins

The release of ACh and other neurotransmitters by exocytosis is inhibited by botulinum and tetanus toxins from Clostridium. Botulinum toxin acts in the nerve ending to reduce ACh vesicular release (see Chapters 9 and 63 for therapeutic uses of botulinum toxin).

Kotter Change Model Penguins

FIGURE 6-3 A cholinergic neuroeffector junction. The synthesis of ACh in the varicosity depends on the uptake of choline via a sodium-dependent carrier. This uptake can be blocked by hemicholinium. Choline and the acetyl moiety of acetyl coenzyme A, derived from mitochondria, form ACh, a process catalyzed by the enzyme choline acetyltransferase (ChAT). ACh is transported into the storage vesicle by a carrier that can be inhibited by vesamicol. ACh is stored in vesicles along with other potential cotransmitters (Co-T) such as ATP and VIP. Release of ACh and the Co-T occurs following depolarization of the membrane, which allows the entry of Ca2+ through voltage-dependent Ca2+ channels. Elevated [Ca2+]in promotes fusion of the vesicular membrane with the cell membrane and exocytosis of vesicular contents. This fusion process involves the interaction of specialized proteins of the vesicular membrane (VAMPs, vesicle-associated membrane proteins) and the membrane of the varicosity (SNAPs, synaptosome-associated proteins). The exocytotic release of ACh can be blocked by botulinum toxin. Once released, ACh can interact with the muscarinic receptors (mAChR), which are GPCRs, or nicotinic receptors (nAChR), which are ligand-gated ion channels, to produce the characteristic response of the effector. ACh also can act on presynaptic mAChRs or nAChRs to modify its own release. The action of ACh is terminated by hydrolysis to choline and acetate by acetylcholinesterase (AChE) associated with the effector cell membrane.

FIGURE 6-3 A cholinergic neuroeffector junction. The synthesis of ACh in the varicosity depends on the uptake of choline via a sodium-dependent carrier. This uptake can be blocked by hemicholinium. Choline and the acetyl moiety of acetyl coenzyme A, derived from mitochondria, form ACh, a process catalyzed by the enzyme choline acetyltransferase (ChAT). ACh is transported into the storage vesicle by a carrier that can be inhibited by vesamicol. ACh is stored in vesicles along with other potential cotransmitters (Co-T) such as ATP and VIP. Release of ACh and the Co-T occurs following depolarization of the membrane, which allows the entry of Ca2+ through voltage-dependent Ca2+ channels. Elevated [Ca2+]in promotes fusion of the vesicular membrane with the cell membrane and exocytosis of vesicular contents. This fusion process involves the interaction of specialized proteins of the vesicular membrane (VAMPs, vesicle-associated membrane proteins) and the membrane of the varicosity (SNAPs, synaptosome-associated proteins). The exocytotic release of ACh can be blocked by botulinum toxin. Once released, ACh can interact with the muscarinic receptors (mAChR), which are GPCRs, or nicotinic receptors (nAChR), which are ligand-gated ion channels, to produce the characteristic response of the effector. ACh also can act on presynaptic mAChRs or nAChRs to modify its own release. The action of ACh is terminated by hydrolysis to choline and acetate by acetylcholinesterase (AChE) associated with the effector cell membrane.

By contrast, tetanus toxin primarily has a central action: it is transported in retrograde fashion up the motor neuron to its soma in the spinal cord. From there the toxin migrates to inhibitory neurons that synapse with the motor neuron and blocks exocytosis in the inhibitory neuron. The block of release of inhibitory transmitter gives rise to tetanus or spastic paralysis. The toxin from the venom of black widow spiders (a-latrotoxin) binds to neurexins, transmembrane proteins that reside on the nerve terminal membrane, resulting in massive synaptic vesicle exocytosis.

ACETYLCHOLINESTERASE (AChE)

ACh must be removed or inactivated within the time limits imposed by the response characteristics of the synapse. At the neuromuscular junction, immediate removal is required to prevent lateral diffusion and sequential activation of adjacent receptors. This removal is accomplished in <1 ms by hydrolysis of ACh by AChE. The Km of AChE for ACh is ~50-100 mM. The resulting choline has only 10-3-10-5 the potency of ACh at the neuromuscular junction. AChE is found in cholinergic neurons (dendrites, perikarya, and axons) and is highly concentrated at the post-synaptic end plate of the neuromuscular junction. A similar esterase, butyrylcholinesterase (BuChE; also known as pseudocholinesterase), is present in low abundance in glial or satellite cells but is virtually absent in neuronal elements of the central and peripheral nervous systems.

BuChE is synthesized primarily in the liver and is found in liver and plasma. AChE and BuChE typically are distinguished by the relative rates of ACh and butyrylcholine hydrolysis and by effects of selective inhibitors (see Chapter 8). Almost all pharmacological effects of the anti-ChE agents are due to the inhibition of AChE, with the consequent accumulation of endogenous ACh in the vicinity of the nerve terminal.

CHARACTERISTICS OF CHOLINERGIC TRANSMISSION AT VARIOUS SITES Skeletal Muscle

At the neuromuscular junction (Figure 9—2), ACh interacts with nicotinic ACh receptors and induces an immediate, marked increase in cation permeability. Upon activation by ACh, the nicotinic receptor's intrinsic channel opens for about 1 ms, admitting ~50,000 Na+ ions. The channel-opening process is the basis for the localized depolarizing EPP within the end plate, which triggers the muscle AP and leads to contraction.

Autonomic Ganglia

The primary pathway of cholinergic transmission in autonomic ganglia is similar to that at the neuromuscular junction of skeletal muscle. The initial depolarization is the result of activation of nicotinic ACh receptors, which are ligand-gated cation channels with properties similar to those found at the neuromuscular junction. Several secondary transmitters or modulators either enhance or diminish the sensitivity of the postganglionic cell to ACh. Ganglionic transmission is discussed in more detail in Chapter 9.

Autonomic Effectors

Stimulation or inhibition of autonomic effector cells by ACh results from interaction of ACh with muscarinic ACh receptors. In this case, the effector is coupled to the receptor by a G protein (see Chapter 1). In contrast to skeletal muscle and neurons, smooth muscle and the cardiac conduction system (sinoatrial [SA] node, atrium, atrioventricular [AV] node, and the His-Purkinje system) normally exhibit intrinsic activity, both electrical and mechanical, that is modulated but not initiated by nerve impulses. At some smooth muscle, ACh causes a decrease in the resting potential (i.e., the membrane potential becomes less negative) and an increase in the frequency of spike production, accompanied by a rise in tension. A primary action of ACh in initiating these effects through muscarinic receptors is probably partial depolarization of the cell membrane brought about by an increase in Na+ and, in some instances, Ca2+ conductance; activation of muscarinic receptors can also activate the Gq-PLC-IP3 pathway leading to the mobilization of stored Ca2+. Hence, ACh stimulates ion fluxes across membranes and/or mobilizes intracellular Ca2+ to cause contraction.

In the heart, spontaneous depolarizations normally arise from the SA node. In the cardiac conduction system, particularly in the SA and AV nodes, stimulation of the cholinergic innervation or the direct application of ACh causes inhibition, associated with hyperpolarization of the membrane and a marked decrease in the rate of depolarization. These effects are due, at least partly, to a selective increase in permeability to K+ and are mediated by muscarinic cholinergic receptors.

Think Clean and Green to Flawless Skin

Think Clean and Green to Flawless Skin

Lets accept the fact: many of us are skin conscious. As much as possible, we wanted to have a fresh, good looking skin. However, many of us failed to recognize that simple steps are the best ways to attain it.

Get My Free Ebook


Post a comment