Biomedical Engineering Reference
In-Depth Information
16.5 NICOTINIC ACh RECEPTORS
The nAChRs belong to the superfamily of ligand-gated ion channels termed “Cys-loop receptors”
(Chapter 12). The receptors are complexes composed of i ve subunits forming an ion pore through
which Na
+
and Ca
2+
ions can enter the cell when the receptor is activated, resulting in depolarization
of the neuron and increased intracellular Ca
2+
concentrations.
To date 17 different nAChR subunits have been identii ed (Figure 16.12A). The “muscle-type
nAChR” is composed of a
1
, b
1
, d, and g/e subunits and is localized postsynaptically at the neuro-
muscular junction (Figure 16.12B). The receptor is a key mediator of the electrical transmission
across the anatomical gap between the motor nerve and the skeletal muscle, thus creating the skel-
etal muscle tone. Hence, antagonists of this receptor are used clinically as muscle relaxants during
anesthesia. The “neuronal nAChRs” are heteromeric or homomeric complexes composed of the
a
2
-a
10
and b
2
-b
4
subunits (Figure 16.12B), and they are located at presynaptic and postsynaptic
densities in autonomic ganglia and in cholinergic neurons throughout the CNS. Equally important
to the overall contribution of nAChRs to cholinergic neurotransmission are the roles of nAChRs as
autoreceptors and heteroreceptors regulating the synaptic release of ACh and other important neu-
rotransmitters such as dopamine, noradrenalin, serotonin, glutamate, and GABA.
The 12 neuronal nAChR subunits display considerable different expression patterns in the CNS,
and this combined with the ability of the subunits to assemble into a vast number of different combi-
nations characterized by signii cantly different pharmacological proi les give rise to a large degree
of heterogeneity in the native receptor populations. The two predominant physiological neuronal
nAChRs are the heteromeric a
4
b
2
subtype and the homomeric a
7
receptor. The a
4
b
2
subtype con-
stitutes >90% of the high-afi nity binding sites for nicotine in the brain and is the most obvious
nAChR candidate in the treatment of AD and nicotine addiction. The homomeric a
7
nAChR is
characterized by its low binding afi nities for the classical nAChR ligands, by fast desensitization
kinetics, and by a remarkable high Ca
2+
conductance. In recent years, the a
7
nAChR has attracted
considerable attention as a drug target for the treatment of states of inl ammation, the i bromyalgia
syndrome and various forms of pain, and modulation of a
7
signaling appears to be benei cial in
particular for the cognitive and sensory impairments observed in schizophrenia. Although the two
major neuronal nAChR subtypes have attracted most of the attention in terms of development of
nAChR-based therapeutics, several of the “minor” subtypes are also interesting targets. For example,
the a
6
subunit is localized exclusively in the midbrain, and a
6
-containing nAChR subtypes have
been shown to regulate synaptic dopamine release in striatum making them interesting in relation
to Parkinson's disease (Chapter 17).
α
7
α
9
α
10
β
1
δ
α
β
1
α
α
1
α
β
β
2
β
4
α
1
α
5
δ
α
β
γ/ε
α
β
3
β
α
2
α
α
1
α
4
α
α
3
α
6
Muscle-type nAChRs
[α
1
, β
1
, δ, γ, ε]
Heteromeric neuronal nAChRs
[α
2
-α
6
, β
2
-β
4
]
Homomeric neuronal nAChRs
[α
7
, α
9
]
(A)
(B)
FIGURE 16.12
The nAChR family. (A) A phylogenetic tree over the nAChR family. (B) The multiple
nAChR complexes formed by the 17 subunits. The localization of the orthosteric sites in the respective recep-
tors is indicated.
