Nicotinic depolarization

Stevens, D. R., Birnstiel, S., Gerber, U., McCarley, R. W. Greene, R. W. (1993). Nicotinic depolarizations of rat medial pontine reticular formation neurons studied in vitro. Neuroscience 57, 419-24. 

Edrophonium is also used to assess the adequacy of treatment with the longer-acting cholinesterase inhibitors in patients with myasthenia gravis. If excessive amounts of cholinesterase inhibitor have been used, patients may become paradoxically weak because of nicotinic depolarizing blockade of the motor end plate. 

As it exerts an initial action of nicotinic depolarization at the motor end-plate membrane it is regarded as a depolarizing neuromuscular relaxant. It is used as a muscle relaxant especially for comparatively short surgical operations and, also for manipulative procedures. 

It cannot undergo hydrolysis in the presence of cholinesterase and, therefore, gives rise to an appreciable prolonged duration of action. It is usually considered to be a depolarizing nemomuscular relaxant by virtue of the fact that it initiates an action of nicotinic depolarization at the site of motor end-plate membrane. 

The AMPA receptors for glutamate, the nicotinic acetylcholine receptor and the 5-HT3-receptor for serotonin are cation channels (Table 1). When they open, the major consequence is a sudden entry of Na+, depolarization and an excitatory postsynaptic potential (EPSP Fig. 1). 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

All cell membranes contain transmembrane proteins that form ion channels. These ion channels are usually selectively permeable to particular ions. Some channels, such as GABA-gated ion channels, are permeable to Cl ions and are inhibitory in nature because they make the inside of the nerve or muscle cells more negative as the Cl ions enter. Some ion channels are permeable to the cations Na and K, and an example of this type is the nicotinic acetylcholine-gated channel. Nicotinic channels have an excitatory effect when they open because Na ions enter and K ions leave through these channels. The cell becomes more positive inside and depolarizes. If the cell is a muscle cell, calcium accumulates in the cytoplasm and it contracts. We have found that all over the surface of Ascaris muscle there are GABA receptors (Martin, 1980) as well as nicotinic acetylcholine channels (Martin, 1982 Robertson and Martin, 1993). 

Nicotine is an agonist at the nicotinic acetylcholine receptor (nAChR). Activation of this receptor depolarizes target cells (see Ch. 11). nAChRs are composed of five subunits surrounding a central ion-channel pore. Twelve different nicotinic receptor subunits are expressed in the nervous system (a2-oclO and (32—134). Of these, a subset is expressed in the VTA (a3-a7 and P2—134). It is thought that a7 receptors form homomeric receptors a3, a4 and a6 form heteromeric channels with 02 or 04 and a5 and 03 can associate with other a/0 pairs. Studies in knockout mice implicate several subunits in the ability of nicotine to modulate dopamine neurons (a4, a6, a7, 02, 03) but... 

An example of a ligand-gated ion channel (B) is the nicotinic cholinocep-tor of the motor endplate. The receptor complex consists of five subunits, each of which contains four transmembrane domains. Simultaneous binding of two acetylcholine (ACh) molecules to the two a-subunits results in opening of the ion channel, with entry of Na+ (and exit of some 1<+), membrane depolarization, and triggering of an action potential (p. 

At a low concentration, the tobacco alkaloid nicotine acts as a ganglionic stimulant by causing a partial depolarization via activation of ganglionic cholinocep-tors (p. 108). A similar action is evident at diverse other neural sites, considered below in more detail. 

Neuromuscular transmission (B) of motor nerve impulses to the striated muscle fiber takes place at the motor endplate. The nerve impulse liberates acetylcholine (ACh) from the axon terminal. ACh binds to nicotinic cholinocep-tors at the motor endplate. Activation of these receptors causes depolarization of the endplate, from which a propagated action potential (AP) is elicited in the surrounding sarcolemma. The AP triggers a release of Ca from its storage organelles, the sarcoplasmic reticulum (SR), within the muscle fiber the rise in Ca concentration induces a contraction of the myofilaments (electromechanical coupling). Meanwhile, ACh is hydrolyzed by acetylcholinesterase (p. 100) excitation of the endplate subsides. if no AP follows, Ca + is taken up again by the SR and the myofilaments relax. 

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