J Mol Neurosci (2010) 41:340–346
DOI 10.1007/s12031-010-9377-2
Muscarinic Acetylcholine Receptors (mAChRs)
in the Nervous System: Some Functions and Mechanisms
David A. Brown
Received: 13 April 2010 / Accepted: 16 April 2010 / Published online: 6 May 2010
# Springer Science+Business Media, LLC 2010
Abstract This article summarizes some of the effects of
stimulating muscarinic receptors on nerve cell activity as
observed by recording from single nerve cells and
cholinergic synapses in the peripheral and central nervous
sytems. It addresses the nature of the muscarinic receptor(s)
involved and the ion channels and subcellular mechanisms
responsible for the effects. The article concentrates on three
effects: postsynaptic excitation, postsynaptic inhibition, and
presynaptic (auto) inhibition. Postsynaptic excitation results
primarily from the inhibition of potassium currents by M1/
M3/M5 receptors, consequent upon activation of phospholipase C by the G protein Gq. Postsynaptic inhibition results
from M2-activation of inward rectifier potassium channels,
consequent upon activation of Gi. Presynaptic inhibition
results from M2 or M4 inhibition of voltage-gated calcium
channels, consequent upon activation of Go. The segregation receptors, G proteins and ion channels, and the
corelease of acetylcholine and glutamate from cholinergic
fibres in the brain are also discussed.
Keywords Acetylcholine . Muscarinic receptors .
G proteins . Potassium channels . Calcium channels .
Corelease
In 1914, Dale classified the actions of acetylcholine (ACh)
into nicotine-like and muscarine-like. We would now say
that this resulted from an action on nicotinic or muscarinic
receptors. Further, so far as the brain is concerned (and in
spite of the resurgence of interest in nicotinic receptors,
This paper is part of the conference of Proceedings of the XIII
International Symposium on Cholinergic Mechanisms
D. A. Brown (*)
Department of Neuroscience, Physiology and Pharmacology,
University College London,
Gower Street,
London WC1E 6BT, UK
e-mail: d.a.brown@ucl.ac.uk
as indicated by the contents of this Symposium), it is the
muscarinic receptor that is the most abundant and
functionally predominant.
Muscarinic receptors belong to the class of heptahelical
G protein-coupled receptors. There are five subtypes, M1M5 (Hulme et al. 1990; Caulfield and Birdsall 1998). Oddnumbered ones (M1, M3, and M5) couple preferentially to G
proteins of the Gq/11 family (Pertussis toxin-insensitive),
even-numbered ones (M2 and M4) to the Gi/Go (Pertussis
toxin-sensitive) family of G proteins, though the functional
coupling will also depend on relative abundance. Many
nerve cells contain more than one subtype, some up to four
(Hassall et al. 1993).
In order for the activation of the receptor to be
transduced into a change in nerve cell activity, in the
short term at least the activated G protein has to alter the
activity of one or more ion channels in the nerve cell
membrane. Table 1 lists some of the common ion channel
responses to mAChR stimulation with their principal
consequences (see Caulfield 1993; Brown et al. 1997 for
some details).
In the ensuing account, I consider three functional
responses to mAChR stimulation resulting from these ion
channel effects—postsynaptic excitation, postsynaptic
inhibition, and presynaptic inhibition (‘auto-inhibition’).
Postsynaptic Excitation
This was initially identified in experiments on sympathetic
ganglia, as an atropine-sensitive slow after-depolarization
(slow excitatory post-synaptic potential, s-epsp) and
delayed spike discharge following the nicotinic response
to repetitive preganglionic stimulation (Fig. 1A; see Kuba
and Koketsu 1978, for review of early experiments).
Similar events were subsequently recorded in central
neurons—for example, in hipocampal pyramidal cells
J Mol Neurosci (2010) 41:340–346
341
Table 1 Coupling of mAChRs to neural ion channels: some examples
Receptor subtype
G protein
Messenger system
Ion channel response
Nerve cell response
Notes
M1, M3, M5
Gq/11
Gα: PIP2 hydrolysis
M2, M4
Gi/o
Gβγ: direct action
KV7 (KM) inhibition
KsAHP inhibition
Kleak inhibition
Cation channel activation
CaV inhibition
CaV2 inhibition
Kir3 activation
Depolarization, increased excitability
Increased excitability
Depolarization
Depolarization, increased excitability
?
Presynaptic inhibition
Postsynaptic inhibition
1
2
3
4
5
6
7
1. Prominent in sympathetic neurons and some central neurons (hippocampal and cortical pyramidal neurons, striatal medium spiny neurons).
Results from reduction of membrane PIP2 levels
2. Prominent in some sympathetic neurons and in cortical and hippocampal pyramidal neurons. KsAHP is a Ca2+ -activated K+ channel (molecular
identity unknown) that generates a slow (seconds-long) spike after-hyperpolarization (sAHP)
3. Observed in some central and peripheral neurons. The nature of the channel is unknown (possibly TASK1/3: Broicher et al. 2008)
4. Observed in some peripheral and central neurons. The nature of the channel is unknown (possibly NALCN: Lu et al. 2009)
5. Indirect voltage-independent inhibition of CaV1 and CaV2 channels (see note 6), probably resulting from reduction of PIP2 (see note 1).
Functional significance not very clear but could potentially contribute to enhanced postsynaptic excitability and possibly reduced transmitter
release, though no evidence for this as yet
6. Direct voltage-dependent effect of the βγ subunit on CaV α-subunit. Principal cause of presynaptic auto-inhibition
7. Direct activation of Kir3.1/3.2 channels by the βγ subunits. Generates an inhibitory postsynaptic hyperpolarization at restricted sites in the
nervous system
A
B
stimulate
stimulate
record
record
b1
a
5 mV
10 mV
V
V
b2
I
0.5 nA
I
b3
0.25 nA
1 min
0.5 nA
1 min
Figure 1 Slow synaptic excitatory potentials (V) and currents (I)
recorded from: A a neuron in an isolated rat sympathetic ganglion
following preganglionic stimulation and B a hippocampal pyramidal
neuron by stimulating fibres from the medial septum in a rat septohippocampal slice co-culture. A Microelectrode recording in the
presence of 0.3 mM d-tubocurarine and 1 µM neostigmine. Nerve
stimulated at 20 Hz for 5 s. Resting potential and clamp potential
−47 mV (from Fig. 11 in Brown and Selyanko 1985). B Microelectrode recording from a CA3 pyramidal neuron following stimulation
of the septo-hippocampal fibre outgrowth with a 1 s train of stimuli at
40 Hz. Records in b show evoked currents before (b1) and after
adding 1 μM neostigmine (b2) and then 1 μM atropine (b3). [From
Figs. 2 and 3 in Gahwiler and Brown 1985.]
342
J Mol Neurosci (2010) 41:340–346
following stimulation of the cholinergic septal inputs (Cole
and Nicoll 1984; Gahwiler and Brown 1985; see Fig. 1B).
Likewise, the molecular mechanism responsible for this
event has been analysed in most detail in sympathetic
neurons, but applies at least in part to central neurons.
Thus, the muscarinic excitatory response of sympathetic neurons is primarily due to inhibition of a subset
of subthreshold voltage-gated K+ channels termed ‘Mchannels’ (Brown and Adams 1980). These channels are
now known to be composed of subunits of the KV7 family
of K+ channels—principally KV7.2 and KV7.3 (Wang et
al. 1998). Though ‘gated’ by voltage, they require an
adequate density of the phospholipid phosphatidylinositol4,5-bisphosphate (PIP2) in the inner membrane leaflet for
the open state to be stabilised (see Suh and Hille 2005;
Gamper and Shapiro 2007). Through coupling to Gq, M1mAChRs activate phospholipase Cβ, and hence produce a
rapid hydrolysis of PIP2; channels then close because of
the net depletion of membrane PIP2 (Brown et al. 2007;
see Fig. 2). This fall in PIP2 is profound (>90 %) and
rapid, giving a latency to channel closure of ∼250 ms.
M-channel closure has two main consequences for the
sympathetic neuron. First, it causes an inward (depolarizing)
current (Fig. 2B) whose magnitude depends on membrane
voltage. Because a few channels are open at rest, their
closure is the cause of the s-epsc and s-epsp illustrated in
Fig. 1A. Second, and more importantly, when the membrane
is depolarized, more channels open and normally this serves
to reduce the excitability of the cell (manifested in Fig. 2 as
an arrest of repetitive spike discharges); this ‘brake’ is lost
when they are closed by mAChR activation, leading to
increased activity. The same effects are seen when the
channels are blocked directly with a channel blocker (Zaika
et al. 2006).
M-channel closure also contributes to the muscarinic
ecitation of central neurons (e.g., hippocampal pyramidal
neurons: Halliwell and Adams 1982; cortical pyramidal
neurons: McCormick and Williamson 1989), and is
mediated by the same molecular mechanism (e.g., Shen et
al. 2005). However, the overall response of most central
neurons is more complex than that of sympathetic neurons.
Thus, in addition to the increased firing activity, closure can
A
A
B
Gαq
control
a
agonist
M1-mAChR
a
PLC
PIP2
K+
Gi antisense
X
PIP2
b
DAG
IP3
b
transducin
-30 mV
c
B
40 mV
-50 mV
1s
1s
3 min
C
-55 mV
1s
muscarine
Figure 2 M1-mAChRs close M-channels in sympathetic neurons by
stimulating hydrolysis of PIP2. A Channels require PIP2 to stabilise
open state. M1-mAChR stimulation induces hydrolysis of PIP2 via
Gαq-PLCβ activation and reduces PIP2 levels so channels close (X).
B Closure is seen as loss of outward current at −30 mV and loss of Mcurrent deactivation . reactivation transients on stepping to −50 mV. c
M-current normally prevents repetitive action potential firing during
sustained depolarization. After M-channel closure the neuron is
depolarized and can now fire repetitively (records in B and C adapted
from Fig. 2 in Brown et al. 2007)
Figure 3 Postsynaptic inhibitory action and K+ current activation by
mAChR-stimulation. A Membrane hyperpolarization (a) and inhibition of action potential discharges (b) in a frog lumber sympathetic
neuron produced by repetitive stimulation of its afferent input. (The
first two responses in a are post-spike hyperpoloarizations following
antidromic sciatic nerve stimulation. The tonic discharge in B was
induced by a 4-min period of prior stimulation. In both experiments,
the ganglion was treated with d-tubocurarine to suppress nicotinic
reponses. [Adapted from Figs. 8 and 16 in Dodd and Horn 1983.] B
Carbachol (CCh) enhances the inward rectifier current (recorded with
a 1 s ramp depolarization from −140 to −40 mV) in a rat sympathetic
neuron transfected with Kir 3.1 and 3.2 cDNAs (a). This is prevented
by antisense suppression of Giα (b) or sequestration of G protein βγ
subunits with α-tranducin (c). Note: this current is probably the K+
current responsible for the effects shown in a. (adapted from Figs. 1
and 3 in Fernandez-Fernandez et al. 2001)
J Mol Neurosci (2010) 41:340–346
343
also result in epileptiform-burst generation since bursting is
normally suppressed by increased post-spike M-channel
activity (Chen and Yaari 2008). Further, the channels
themselves are concentrated at the axon initial segment
where they control the action potential threshold; hence,
when they are inhibited by mAChR stimulation, the spike
threshold is reduced and this, coupled with the membrane
depolarization, can lead to spontaneous action potential
firing (Shah et al. 2008). A further complication is that
mAChR stimulation affects other membrane currents in
central neurons—in particular, it also leads to the
inhibition of a set of Ca2+-dependent K+ channels that
are activated by the Ca2+ entry during the action potential;
these normally constitute an additional brake on repetitive
action potential discharges so their inhibition further
enhances the excitability of e.g., hippocampal and cortical
pyramidal neurons (Nicoll 1985).
(Dodd and Horn 1983; see Fig. 3A). This hyperpolarization
then inhibits the on-going activity of the ganglion cell
(Fig. 3A (b)). Thus, it bears a close resemblance to the
cardiac response to vagal stimulation and—like the latter—
results from activation of G protein-gated inward rectifier K+
channels (principally Kir3.1 and Kir3.2) by G protein βγsubunits following activation of Gi by M2 mAChRs (see
Wickman and Clapham 1995). Thus, in rat sympathetic
neurons (which do not normally express inward rectifier
channels), the relevant channels can be expressed by cotransfecting Kir3.1 and 3.2 cDNAs and are then activated by
stimulating endogenous M2-receptors (Fig. 3B(a)). This
response is inhibited by antisense depletion of Gi
(Fig. 3B(b)) but not of Go, or by expressing peptides that
sequester G protein βγ-subunits (Fig. 3B(c); see FernandezFernandez et al. 2001). Similar M2 mAChR-mediated effects
of ACh have been detected in some central neurons such as
thalamic reticular neurons (McCormick and Prince 1986)
and parabrachial motor neurons (Egan and North 1986).
Postsynaptic Inhibition
Again the sympathetic (and parasympathetic) neuron provides
the prototype for this response (Kuba and Koketsu 1978). In
bullfrog sympathetic neurons, this event—the ‘slow inhibitory post-synaptic potential’ (s-ipsp)—comprises a delayed
hyperpolarization starting some 50 ms after the nicotinic
epsp, which is generated by an increased K+ conductance
A
Presynaptic Inhibition
One of the most striking aspects of muscarinic transmission—
especially in the brain—is that the release of ACh is subject to
profound ongoing auto-inhibition as a result of co-activation
of presynaptic mAChRs. This was vividly shown 40 years
B
b
c
a
C
muscarine
a
b
b
a
Figure 4 Presynaptic inhibition of ACh release from cholinergic
cortical afferent fibres. A Block of presynaptic mAChRs with atropine
enhances the overflow of ACh from the surface of the cat parietal
cortex induced by reticular formation (RF) stimulation. LOC local
intracortical stimulation (from Fig. 7 in Dudar and Szerb 1969). B, C
Suppression of action potential-evoked ACh release from the neurites
of rat cholinergic basal forebrain (BF) neurons by a muscarinic
agonist. B An action potential (b) is generated in the soma of a
cultured neuron (a). Consequent ACh release is detected as a shortlatency cluster of nicotinic channel openings (c) in a patch electrode
bearing a membrane patch from a rat myotube and placed adjacent to
a release varicosity on a BF neurite. This release is suppressed by
10 μM muscarine (c inset—expanded records of responses a and b; a
from Allen 1997, c from Allen and Brown 1996)
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J Mol Neurosci (2010) 41:340–346
mediated by M2-mAChRs since it was blocked by 100 nM
methoctramine but unaffected by 100 nM pirenzepine (Allen
and Brown 1996). In accord with this, muscarinic inhibition
of 3H-ACh from K+-depolarized cortical slices is lost in
slices from M2-mAChR knock-out mice (Zhang et al. 2002).
The mechanism of presynaptic auto-inhibition in BF
neurons cannot be directly addressed in these small
varicosities but is very likely due to inhibition of Ca2+-entry
through voltage-gated Ca2+ channels. Thus, the somata of
these neurons also express M2-mAChRs and stimulation
of these produced a profound voltage-dependent inhibition
of the N- and P/Q-type (CaV2.2 and CaV2.1) Ca2+-currents
(Allen and Brown 1993; Allen 1999). By analogy with the
more intensively studied voltage-dependent M4 mAChRinduced Ca2+-current inhibition in sympathetic neurons (e.g.,
Delmas et al. 1998), this probably results from mAChRactivation of the G protein Go and consequent direct
interaction of the Go-associated βγ-subunits with the Ca2+
channels. However, additional effects on the release process
downstream to Ca2+ entry (Blackmer et al. 2001) cannot be
excluded.
ago by Dudar and Szerb (1969) as a threefold increase in
the overflow of ACh from the cerebral cortex induced by
afferent (reticular formation) stimulation after adding
atropine (Fig. 4A).
Because of the slow and indirect nature of the
postsynaptic response (see above) it is not possible to
study the mechanisms responsible for this by the
electrophysiological methods normally used at synapses.
To circumvent this we created an artificial nicotinic
junction by culturing basal forebrain (BF) neurons (the
major source of cholinergic afferents to the cortex) and
then applying a membrane patch isolated from a
myotube and bearing nicotinic receptors (an ACh
‘detector patch’) to the release varicosities along the
outgrowing processes of the BF neuron (Allen and
Brown 1996). Then, when an action potential in the BF
neuron reached the varicosities, it induced the rapid
opening of a cluster of nicotinic channels, signalling the
short-latency release of ACh (Fig. 4B). Release was then
very substantially reduced by superfusing a muscarinic
agonist over the neuron (Fig. 4C). This was most likely
A
Glu release (autaptic current)
B
ACh release (nicotinic current)
glutamate
Fast epsp/spikes
mGluR
AMPA-R
M1/3mAChR
M2mAChR
Slow epsp
ACh
Figure 5 Co-release of ACh and glutamate (Glu) from cholinergic
cortical afferents. A Co-release of glutamate (detected as an autaptic
epsc) and ACh (detected with a nicotine receptor detector-patch, see
Fig. 4) from a single cultured BF neuron. Activation of presynaptic
(M2) mAChRs with 10 μM muscarine equally inhibits the release of
both transmitters. B Projected scheme of dual activation of cortical
neurons by co-releasing BF neurons. Glutamate release induces a fast
AMPA-receptor mediated epsp and spike. This is followed by an ipsp
mediated by GABAergic interneurons, followed by a slow epsp
mediated by ACh acting on M1/M3 mAChRs. Release of ACh
presynaptically then inhibits its own release, and that of glutamate.
Glutamate may also exert some presynaptic inhibitory effect but this is
weaker and more variable than that induced by ACh. (The record
shows the response of a layer V somatosensory neuron to stimulation
of the subjacent grey matter at 20 Hz for 400 ms; records in A from
Allen et al. 2006; record in B from Fig. 1 in Benardo 1993.]
J Mol Neurosci (2010) 41:340–346
Co-release and Cross-inhibition of ACh and Glutamate
Release
Postsynaptic muscarinic responses seen on stimulating
presumed cholinergic inputs in the central nervous system
are invariably preceded by glutamate-mediated events (as
shown, for example, in Fig. 1B), as though the same fibres
might be releasing both ACh and glutamate. This indeed
appears to be the case. Thus, when BF neurons are cultured
in isolation, their processes establish glutamatergic (Glu)
autaptic synapses onto the cell soma, Then following a
single action potential, a Glu-mediated fast synaptic current
can be recorded from the cell soma, while an AChmediated nicotinic current can be simultaneously recorded
from the neurite with a nicotinic receptor detector (Allen et
al. 2006). Hence, the same single neuron releases both
transmitters. Further, both currents are reduced pari passu
on stimulating the presynaptic M2 receptors (see Fig. 5A).
This means that the ACh released from BF fibres can
inhibit both its own release and also that of glutamate
(Fig. 5B): thus, during repetitive stimulation of a BF
neuron, the autaptic Glu currents are enhanced by atropine
and reduced by an anticholinesterase (Allen et al. 2006).
This may be of significance when attempts are made to
enhance central cholinergic transmission, for example in the
treatment of Alzheimer’s disease. In contrast, feedback
inhibition by glutamate seems to be relatively weak,
probably through a paucity of presynaptic inhibitory
glutamate receptors.
Receptor–Effector Segregation
As noted above, both the opening of Kir channels (giving
postsynaptic inhibition) and the reduced opening of Ca2+
channels (producing presynaptic inhibition) are mediated
by βγ subunits associated with Pertussis toxin-sensitive G
proteins (Gi or Go). It might therefore be expected that
either or both events could be indiscriminately induced by
M2 or M4 receptors. Curiously this seems not to be the case
—at least in those neurons where the coupling has been
studied in most detail such as rat sympathetic neurons.
Instead, although these neurons possess both M2 and M4
receptors, Ca2+-current inhibition is triggered exclusively
by the M4 receptor (Bernheim et al. 1992; FernandezFernandez et al. 1999), whereas only the M2 receptor
activates Kir3 channels (Fernandez-Fernandez et al. 1999).
This is not because the receptors are incapable of crosscoupling since M2 receptors (not M4) are responsible for
inhibiting the Ca2+ current in the BF neurons (see above)
and also in mouse sympathetic neurons (Shapiro et al.
1999). Further, discrimination continues at the level of the
G protein, since Ca2+ current inhibition is mediated by βγ
345
subunits associated with Go whereas Kir3 activation
involves Gi, even though both currents are potentially
capable of responding to βγ subunits associated with either
G protein (Fernández-Fernández et al. 2001). Thus, these
two pathways are functionally isolated, as follows:
Postsynaptic inhibition
M 2mAChR
Gi
Gi(βγ)
Kir
Go(βγ)
CaV
Presynaptic inhibition
M4mAChR
Go
It would appear that—in sympathetic neurons at least—
the two receptors, and their cognate G proteins and effector
channels, are segregated from each other into separate
functional ‘microdomains’. It seems important to know
how far this applies to mAChR-effector coupling elsewhere
in the neuraxis and what the mechanism(s) for segregation
might be.
Apologia
In this article, I have tried primarily to integrate some of the
observations my colleagues and I have made over the past
three decades or so into a broad scheme of muscarinic
receptor actions and functions in the nervous system.
Inevitably, this leads to some over-simplification and is
far from a comprehensive account of all their effects. I
apologise to all whose work (for this reason and for reasons
of brevity) have been omitted.
Acknowledgements Work from the author’s laboratory was supported by the U.K. Medical Research Council and the Wellcome
Trust.
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