DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

190 Subtypes of Nicotinic Acetylcholine Receptors. The
nicotinic ACh receptors (nAChRs) are members of a
superfamily of ligand-gated ion channels. The receptors
exist at the skeletal neuromuscular junction, autonomic
ganglia, adrenal medulla, the CNS and in
non-neuronal tissues. The nAChRs are composed of
five homologous subunits organized around a central
pore (see Chaper 11). In general the nAChRs are further
divided into two groups:
SECTION II
NEUROPHARMACOLOGY
• muscle type, found in vertebrate skeletal muscle,
where they mediate transmission at the neuromuscular
junction (NMJ)
• neuronal type, found mainly throughout the peripheral
nervous system, central nervous system, and
also non-neuronal tissues
Both the mAChRs and nAChRs are the natural
targets of ACh, synthesized, stored, and released from
cholinergic neurons as well as numerous pharmacologically
administered drugs (agonists and antagonists),
including the alkaloids muscarine and nicotine.
cDNAs for 17 types of nAChRs subunits have been cloned
from several species. These consist of α subunits (α1-α10) that compose
the main ligand binding sites, β (β1-4), γ, δ, and ε subunits.
The nAChRs have been further divided into two main types based on
different binding properties to the toxin α-bungarotoxin (αβgtx):
1) the αβgtx binding nAChRs, which can be either homopentamers
of α7, α8, or α9 subunits or heteropentamers (e.g., α 2
βε[γ]δ); and 2)
nAChRs that do not bind αβgtx. These contain the α2-α6 and
β2-β4 subunits, exist only as heteropentamers, and bind agonists
with high affinity (Albuquerque et al., 2009).
Muscle-Type nAChRs. In fetal muscle prior to innervation, in adult
muscle after denervation, and in fish electric organs, the nAChR subunit
stoichiometry is (α1) 2
β1γδ, whereas in adult muscle the γ subunit
is replaced by ε to give the (α1) 2
β1εδ stoichiometry (Table 8–2).
The γ/ε and δ subunits are involved together with the α1 subunits in
forming the ligand-binding sites and in the maintenance of cooperative
interactions between the α1 subunit. Different affinities to the
two binding sites are conferred by the presence of different non α-
subunits. Binding of ACh to the αγ and αδ sites is thought to induce
a conformational change predominantly in the α1 subunits which
interacts with the transmembrane region to cause channel opening.
Neuronal-Type nAChRs. Neuronal nAChRs are widely expressed in
peripheral ganglia, the adrenal medulla, numerous areas of the brain,
and non-neuronal cells such as epithelial cells and cells of the
immune system. To date, nine α (α 2
-α 10
) and three β (β 2
-β 4
) subunit
genes have been cloned. The α 7
-α 10
subunits are found either as
homopentamers (of five α 7
, α 8,
and α 9
subunits) or as heteropentamers
of α7, α8, and α 9
/α 10
. By contrast, the α 2
-α 6
and β 2
-β 4
subunits
form heteropentamers usually with (αx) 2
(βy) 3
stoichiometry.
The α 5
and β 3
subunits do not appear to be able to form functional
receptors when expressed alone or in paired combinations with α or
β subunits, respectively (Kalamida et al., 2007).
The precise function of many of the neuronal nAChRs in the
brain is not known; presumably, the considerable molecular diversity
of the subunits can result in numerous nAChRs being formed with
different physiological properties. There are few examples of neuronal
nAChRs in the CNS mediating fast signaling propogation in a
manner similar to that at the NMJ, and it is thought that they act
more as synaptic modulators. Neuronal nAChRs are widely distributed
in the CNS and are found at presynaptic, perisynaptic, and postsynaptic
sites. At pre- and perisynaptic sites, nAChRs appear to act
as autoreceptors or heteoreceptors to regulate the release of several
neurotransmitters (ACh, DA, NE, glutamate, and 5-HT) at several
diverse sites throughout the brain (Exley and Cragg, 2008). The
synaptic release of a particular neurotransmitter can be regulated by
different neuronal type nAChR subtypes in different CNS regions.
For instance, DA release from striatal and thalamic dopamine neurons
can be controlled by the α 4
β 2
subtype or both α 4
β 2
and α 6
β 2
β 3
subtypes, respectively. In contrast, glutametergic neurotransmission
is regulated everywhere by α7 nAChRs (Kalamida et al., 2007).
Subtypes of Muscarinic Receptors. In mammals, five distinct
subtypes of muscarinic ACh receptors (mAChRs)
have been identified, each produced by a different gene.
Like the different forms of nicotinic receptors, these variants
have distinct anatomic locations in the periphery and
CNS and differing chemical specificities. The mAChRs
are GPCRs (see Table 8–3 for characteristics of the
mAChRs and Chapter 9 for further details).
Different experimental approaches including immunohistochemical
and mRNA hybridization studies have shown that mAChRs
are present in virtually all organs, tissues, and cell types (Table 8–3).
Although most cell types have multiple mAChR subtypes, certain
subtypes often predominate in specific sites. For example, the M 2
receptor is the predominant subtype in the heart and in CNS neurons
is mostly located presynaptically, whereas the M 3
receptor is
the predominant subtype in the detrusor muscle of the bladder
(Dhein et al., 2001; Fetscher et al., 2002) (see Table 8–3). M 1
, M 4
,
and M 5
receptors are richly expressed in the CNS, whereas the M 2
and M 4
receptor subtypes are widely distributed both in the CNS and
peripheral tissue (Wess et al., 2007). M 3
receptors are widely distributed
in the periphery, and although they are also widely distributed
in the CNS, they are at lower levels than other subtypes.
In the periphery, mAChRs mediate the classical muscarinic
actions of ACh in organs and tissues innervated by parasympathetic
nerves, although receptors may be present at sites that lack parasympathetic
innervation (e.g., most blood vessels). In the CNS, mAChRs
are involved in regulating a large number of cognitive, behavioral,
sensory, motor, and autonomic functions. Owing to the lack of specific
muscarinic agonists and antagonists that demonstrate selectivity
for individual mAChRs and the fact that most organs and tissues
express multiple mAChRs, it has been a challenge to assign specific
pharmacological functions to distinct mAChRs. The development of
gene-targeting techniques in mice has been very helpful in defining
specific functions (Table 8–3) (Wess, 2004).
The basic functions of muscarinic cholinergic
receptors are mediated by interactions with G proteins