cholinergic receptors

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 on 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 their contents into the synaptic space. This release can be blocked by botulinum toxin. In

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contrast, the toxin in black widow spider venom causes all the acetylcholine stored in synaptic vesicles to empty into the synaptic gap.

Figure 4.2 Sites of actions of cholinergic agonists in the autonomic and somatic nervous systems.

Binding to the receptor: Acetylcholine released from the synaptic vesicles diffuses across the synaptic space, and it binds to either of two postsynaptic receptors on the target cell or to presynaptic receptors in the membrane of the neuron that released the acetylcholine. The postsynaptic cholinergic receptors on the surface of the effector organs are divided into two classes⬠muscarinic and nicotinic. (see Figure 4.2 and p. 46). Binding to a receptor leads to a biologic response within the cell, such as the initiation of a nerve impulse in a postganglionic fiber or activation of specific enzymes in effector cells as mediated by second-messenger molecules (see p. 27 and below).

Degradation of acetylcholine: The signal at the postjunctional effector site is rapidly terminated, because acetylcholinesterase cleaves acetylcholine to choline and acetate in the synaptic cleft (see Figure 4.3). [Note: Butyrylcholinesterase, sometimes called pseudocholinesterase,

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is found in the plasma, but it does not play a significant role in termination of acetylcholine's effect in the synapse.]

Figure 4.3 Synthesis and release of acetylcholine from the cholinergic neuron. AcCoA = acetyl coenzyme A.

Recycling of choline: Choline may be recaptured by a sodium-coupled, high-affinity uptake system that transports the molecule back into the neuron, where it is acetylated into acetylcholine that is stored until released by a subsequent action potential.

III. Cholinergic Receptors (Cholinoceptors)

Two families of cholinoceptors, designated muscarinic and nicotinic receptors, can be distinguished from each other on the basis of their different affinities for agents that mimic the action of acetylcholine (cholinomimetic agents or parasympathomimetics).

Figure 4.4 Types of cholinergic receptors.

A. Muscarinic receptors

These receptors, in addition to binding acetylcholine, also recognize muscarine, an alkaloid that is present in certain poisonous mushrooms. By contrast, the muscarinic receptors show only a weak affinity for nicotine (Figure 4.4A). Binding studies and specific inhibitors, as well as cDNA characterization, have distinguished five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5. Although five muscarinic receptors have been identified by gene cloning, only M1, M2 and M3, receptors have been functionally characterized.

Locations of muscarinic receptors: These receptors have been found on ganglia of the peripheral nervous system and on the autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine glands (see Figure 3.3, p. 37). Specifically, although all five subtypes have been found on neurons, M1 receptors are also found on gastric parietal cells, M2 receptors on cardiac cells and smooth muscle, and M3 receptors on the bladder, exocrine glands, and smooth muscle. [Note: Drugs with muscarinic actions preferentially stimulate muscarinic receptors on these tissues, but at high concentration they may show some activity at nicotinic receptors.]