1IRCCS S. Lucia; 2Clinica Neurologica, Università di Tor Vergata, 00179 Rome, Italy; and 3Brain Science Institute, Wako-shi, Saitama 351-0198, Japan
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ABSTRACT |
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Guatteo, Ezia,
Nicola B. Mercuri,
Giorgio Bernardi, and
Thomas Knöpfel.
Group I Metabotropic Glutamate Receptors Mediate an Inward
Current in Rat Substantia Nigra Dopamine Neurons That Is Independent
From Calcium Mobilization.
J. Neurophysiol. 82: 1974-1981, 1999.
Metabotropic glutamate receptors
modulate neuronal excitability via a multitude of mechanisms, and they
have been implicated in the pathogenesis of neurodegenerative
processes. Here we investigated the responses mediated by group I
metabotropic glutamate receptors (mGluRs) in dopamine neurons of the
rat substantia nigra pars compacta, using whole cell patch-clamp
recordings in combination with microfluorometric measurements of
[Ca2+]i and [Na+]i.
The selective group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (3,5-DHPG) was bath-applied (20 µM, 30 s to 2 min) or applied locally by means of short-lasting (2-4 s) pressure pulses, delivered through an agonist-containing pipette positioned close to the cell body
of the neuron. 3,5-DHPG evoked an inward current characterized by a
transient and a sustained component, the latter of which was uncovered
only with long-lasting agonist applications. The fast component
coincided with a transient elevation of
[Ca2+]i, whereas the total current was
associated with a rise in [Na+]i. These
responses were not affected either by the superfusion of ionotropic
excitatory amino acid antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and D-2-amino-5-phosphono-pentanoic acid
(D-APV), nor by the sodium channel blocker tetrodotoxin
(TTX). (S)--methyl-4-carboxyphenylglycine (S-MCPG) and the more
selective mGluR1 antagonist
7(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate (CPCCOEt)
depressed both 3,5-DHPG-induced inward current components and,
although less effectively, the associated
[Ca2+]i elevations. On repeated agonist
applications the inward current and the calcium transients both
desensitized. The time constant of recovery from desensitization
differed significantly between these two responses, being 67.4 ± 4.4 s for the inward current and 28.6 ± 2.7 s for the
calcium response. Bathing the tissue in a calcium-free/EGTA medium or
adding thapsigargin (1 µM) to the extracellular medium prevented the
generation of the [Ca2+]i transient, but did
not prevent the activation of the inward current. These
electrophysiological and fluorometric results show that the
3,5-DHPG-induced inward current and the
[Ca2+]i elevations are mediated by
independent pathways downstream the activation of mGluR1.
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INTRODUCTION |
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Electrophysiological studies both in vitro and in
vivo have demonstrated that activation of metabotropic glutamate
receptors (mGluRs) induces an excitation of dopamine neurons of the
substantia nigra pars compacta (Meltzer et al. 1997;
Mercuri et al. 1993
). At present, eight different mGluR
subtypes have been cloned, termed mGluR1 through mGluR8. The mGluR
subtypes are classified into three groups, I through III, according to
similarities in their primary structure, signal transduction pathways,
and pharmacology, as derived from cloned receptors that were expressed
in nonneuronal expression systems (Conn and Pin 1997
;
Houamed et al. 1991
; Knöpfel et al.
1995
; Masu et al. 1991
; Nakanishi
1992
). This multitude is further enhanced by the existence of
splice variants of many of the mGluR subtypes. Alternative splicing of
the mGluR1 gene results in the expression of the splice variants
mGluR1a through mGluR1d, which are differentially expressed at the
cellular and at the subcellular level (Ferraguti et al.
1998
; Grandes et al. 1994
; Kosinski et
al. 1998
). Although dopamine cells do not exhibit high levels
of immunoreactivity for the mGluR1a splice variant (Testa et al.
1998
), it has been more recently demonstrated that these cells
predominately express the mGluR1d splice variant (Kosinski et
al. 1998
). Group I mGluRs expressed at the somatodendritic membrane are known to mediate an excitation and increased excitability in a variety of neuron types and by a multitude of mechanisms. These
mechanisms include the depression of potassium conductances (Charpak et al. 1990
), the activation of
calcium-activated unselective cation conductances (Congar et al.
1997
; Crepel et al. 1994
; Raggenbass et
al. 1997
), the activation of calcium-independent unselective cation conductances (Guerineau et al. 1995
), the
up-regulation of calcium channel activity (Chavis et al.
1996
), and the operation of an electrogenic
Na+/Ca2+-exchange
(Keele et al. 1997
; Lee and Boden 1997
;
Staub et al. 1992
). Furthermore, by virtue of their
coupling to phosphoinositide hydrolysis and mobilization of calcium
from intracellular stores, activation of group 1 mGluRs can result in
the activation of calcium-sensitive potassium conductances
(Fagni et al. 1991
; Rainnie et al.1994
). Indeed, an inhibitory action mediated by mGluR1d has recently been
demonstrated in dopamine cells (Fiorillo and Williams
1998
). With regard to the dopamine neurons of the substantia
nigra pars compacta, mGluRs activation determines an inward current
that is principally dependent on the extracellular concentration of sodium ions (Mercuri et al. 1993
). Thus the purpose of
the present study was to further characterize the mGluR-mediated inward
current in dopamine neurons and its possible relation to changes in
[Ca2+]i and
[Na+]i. A particular
emphasis was given to the question whether there is a mechanistic
relationship between the excitation and the Ca2+
signaling pathway that is expectedly activated by group I mGluRs.
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METHODS |
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Electrophysiology
Preparation of rat midbrain slices was performed as described
previously (Lacey et al. 1989; Mercuri et al.
1995
). In brief, horizontal slices including the substantia
nigra and the ventral tegmental area were cut from the ventral
mesencephalon of Wistar rats (150-250 g) anesthetized with halothane
and killed. The brain was rapidly removed, and horizontal slices
(thickness 300 µm) were cut by a vibratome starting from the ventral
surface of the midbrain. A single slice was then transferred into a
recording chamber and completely submerged in an artificial
cerebrospinal fluid with continuously flowing (2.5 ml/min) solution at
35-36°C (pH 7.4). This solution contained (in mM) 126 NaCl, 2.5 KCl,
1.2 MgCl2, 1.2 NaH2PO4, 2.4 CaCl2, 10 glucose, and 18 NaHCO3, gassed with 95%
O2-5% CO2. The recording
chamber was mounted on the stage of an upright microscope (Axioscope
FS, Carl Zeiss) equipped for infrared video microscopy (Hamamatsu,
Hamamatsu City, Japan) and video microfluorometry (ImproVision,
Coventry, UK). Whole cell patch-clamp recordings were obtained from
visually identified dopamine neurons (Bonci and Williams
1996
) using pipettes made from borosilicate glass (WPI 1.5 mm)
and pulled with a PP 83 Narishige puller. The resistance of the pipette
was ~4 M
when filled a standard solution containing (in mM) 145 K+-gluconate, 0.1 CaCl2, 2 MgCl2,
10 HEPES, 0.75 EGTA, 2 Mg-ATP, and 0.3 Na3GTP, pH 7.3. For
microfluorometry (see below), 250 µM fura-2, 250 µM sodium-binding
benzofuran isophthalate (SBFI), and/or 125 µM calcium green-1
(Molecular Probes, Leiden, The Netherlands) were added to the pipette
solution. The membrane voltage and current were acquired using pClamp
and Axoscope software (Axon Instruments).
Microfluorometry
Fluorescent ion indicators were excited via a ×40 water
immersion objective (Olympus) by epi-illumination with light provided by a 75-W Xenon lamp. Excitation light was band-pass filtered alternatively at 340 or 380 nm for neurons loaded with fura-2 or SBFI,
at 480 nm for calcium green recordings, and alternatively at 340, 360, 380, and 480 nm for neurons loaded with both calcium green and SBFI.
Emission light passed a barrier filter (500 nm) and was detected by a
charge-coupled device (CCD) camera (Photonic Science, Millham,
UK). A set of images obtained at different excitation wavelengths was
acquired at 6- or 12-s intervals. Time courses of fluorescence values
obtained at a given excitation wavelength were calculated over regions
that included the cell bodies ("regions of interest," defined as
those pixels that exhibit at least 20-30% of maximal specific
fluorescence) and were corrected for background fluorescence (measured
from image regions free of dye fluorescence, IonVision software,
ImproVision). For measurements using fura-2 and SBFI the ratio
of fluorescence obtained at excitation wavelengths of 340 and 380 nm
were transformed into ion concentration using the method of
Grynkiewicz (Grynkiewicz et al. 1985). The
calibration of our system has been described previously (Guatteo
et al. 1998
; Knöpfel et al. 1998
).
Recordings of changes of [Ca2+]i using
calcium green are expressed as
F/F
values as described earlier (Muri and Knöpfel
1994
). Analysis and curve fitting was done using Origin 5 software (Microcal, Northampton, MA). Values in the text are
expressed as means ± SE. Student's t-test was used for statistical analysis.
Drug application
(S)-3,5-Dihydroxyphenylglycine (3,5-DHPG),
(S)--methyl-4-carboxyphenylglycine (MCPG),
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX),
D
2-amino-5-phosphono-pentanoic acid (APV), and
7(hydroxyimino) cyclopropa[b]chromen-1a-carboxylate (CPCCOEt) were
obtained from Tocris Cookson (Bristol, UK); tetrodotoxin (TTX) and
thapsigargin were obtained from Calbiochem. All other compounds were
from Sigma. Drugs were bath-applied by switching the solution to one
containing known concentrations of drugs. An exchange of the solution
in the recording chamber occurred in ~1 min. Agonists were also
applied via a patch pipette that was positioned in close vicinity of
the cell body and was connected to a pressure application system
(Picospritzer, 20-30 psi, 0.1-10 s).
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RESULTS |
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The database was derived from 54 visually and
electrophysiologically identified principal neurons of the substantia
nigra pars compacta. The criteria for the electrophysiological
identification of dopamine neurons were, as described previously, a
hyperpolarizing response to dopamine (30 µM) and a pronounced
hyperpolarization-induced slowly relaxing inward current,
Ih (Grace and Onn 1989;
Lacey et al. 1989
; Mercuri et al.
1993
, 1995
; Yung et al.
1991
). Cells were visually identified by their fusiform cell
body and long unbranched proximal dendrites extending in the plane of
the slice (cf. Fig. 1A) (Grace
and Onn 1989
).
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Activation of group I metabotropic glutamate receptors induces an inward current associated with a rise in [Ca2+]i and [Na+]i
About 5-10 min after formation of the whole cell configuration,
the cell bodies and proximal dendrites of the dopamine neurons were
loaded with the fluorescent dye contained in the patch pipette. Figure
1 shows recordings from a neuron loaded with the calcium indicator
fura-2. Bath application of 20 µM 3,5-DHPG, a selective group I mGluR
agonist (Schoepp et al. 1994), induced a biphasic inward
current (Fig. 1B). The first component of the
3,5-DHPG-induced inward current had a mean amplitude of 142 ± 44 pA (mean ± SE, n = 8) and inactivated rapidly in
the presence of the agonist uncovering a second more persistent
component of 69 ± 13.2 pA. These agonist-induced currents were
associated with an elevation in
[Ca2+]i of ~406 ± 106.8 nM (n = 4) when estimated with fura-2 (Fig. 1).
Elevation in [Ca2+]i of
comparable size and decay time course were obtained when the cell was
voltage clamped to
30 mV for 30 s. As illustrated in Fig.
1C, these calcium signals were relatively homogenous over the cell body and initial portion of the proximal dendrites, and time
course analysis was restricted to this part of the neuron. Similar
inward currents and
[Ca2+]i elevations were
obtained with the less selective mGluR agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) (70 µM, cf. Fig. 2C).
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To determine whether the 3,5-DHPG-induced inward current was
associated also with an elevation in [Na+]i,
dopamine neurons were loaded with the Na+-sensitive dye
SBFI. These experiments revealed a large elevation in
[Na+]i during the mGluR-induced inward
current (Fig. 2, A and C). Figure
2B illustrates [Ca2+]i
measurements using only calcium green in the pipette. This Ca2+ dye indicates 3,5-DHPG-induced
[Ca2+]i changes with
F/F values of 0.76 ± 0.2 (n = 7) and whose time courses were consistent with
those obtained with fura-2. To directly compare the time courses of the
[Ca2+]i and the
[Na+]i elevations with the components of the
inward current in the same neuron, we combined SBFI with the indicator
calcium green (Fig. 2C). When comparing the time course
of the mGluR-induced [Ca2+]i and
[Na+]i elevations, either within a single
cell loaded with both dyes (Fig. 2C) or between cells
(Figs. 1 and 2, A and B), it can be clearly seen that the [Na+]i increase relates
to the total inward current, whereas the
[Ca2+]i increase coincided with the initial
transient component of the current. Similar differences in the
agonist-induced time courses of [Na+]i and
[Ca2+]i were observed in all 5/5 cells
recorded with pipettes containing both SBFI and calcium green.
It has been recently reported that 3,5-DHPG can, under certain
conditions, interact with
N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors (Contractor et al. 1998). To
demonstrate that, under the present conditions, 3,5-DHPG does not
activate ionotropic receptors and does not cause opening of
voltage-dependent dendritic channels to produce the inward current and
to increase [Na+]i, we compared 3,5 DHPG-induced responses recorded in the presence of a cocktail of
ionotropic antagonists (50 µM D-APV and 30 µM CNQX) and
in the presence of TTX (1 µM) with responses recorded in the absence
of these channel blockers (Fig. 3). The
DHPG responses were not significantly affected either by the ionotropic
glutamate receptor antagonists nor by TTX (ANOVA, P < 0.05). In the presence of 50 µM D-APV and 30 µM
CNQX, the mean current amplitude amounted to 107 ± 6.1%, and the
mean sodium increase to 111 ± 36.9% of controls
(n = 6; Fig. 3A). In the presence of
1 µM TTX, the mean DHPG-induced current was 86 ± 6.2%, and the
mean sodium increase was 100.6 ± 10.9% (n = 4) of control (Fig. 3B).
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To isolate the initial transient component of the 3,5-DHPG-induced inward current, we applied the agonist via a pipette positioned close to the cell body and subjected to short-lasting (2 s) pressure pulses (see METHODS). Pressure ejection of the group I mGluR agonist induced short-lasting inward currents associated with [Ca2+]i elevations comparable in size with those obtained with bath application of the agonist (Fig. 4A). These transient inward currents were also accompanied by elevations in [Na+]i that, however, required averaging over several agonist puffs to be revealed with a reasonably good signal-to-noise ratio (Fig. 4B, n = 3). The size of these [Na+]i elevations is nevertheless consistent with the level of [Na+]i reached during generation of the initial transient inward currents in the experiments with bath application of the agonist (cf. Fig. 2A).
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MGluR subtype pharmacology
3,5-DHPG is a specific agonist for group I mGluRs, and the
responses described above are therefore most likely mediated by the
mGlu receptor subtypes mGluR1 or mGluR5. To differentiate between these
two subtypes, we took advantage of the fact that the compound CPCOOEt
antagonizes responses mediated by mGluR1 much more potently than those
mediated by mGluR5 (Casabona et al. 1997;
Litschig et al. 1999
). In addition, we compared the antagonism of the 3,5-DHPG-induced effects by CPCOOEt with that obtained with the broad-spectrum antagonist S-MCPG (Watkins and Collingridge 1994
). CPCOOEt applied at a concentration of 100 µM and S-MCPG applied at 700 µM depressed the 3,5-DHPG-induced inward current to 40 ± 4.8% (n = 8) and 43 ± 7.7% (n = 8) of controls, respectively (Fig.
5). Likewise, the calcium elevations were
depressed to a similar extent by 100 µM CPCCOEt and 700 µM S-MCPG
(74.5 ± 9.9 and 72.3 ± 12.1% of controls, respectively,
n = 8, Fig. 5).
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Desensitization of the fast transient inward current and [Ca2+]i elevation
When we used fast pressure application of 3,5-DHPG, we noted that the fast transient inward current, as well as the associated [Ca2+]i elevations, exhibit rapid desensitization on repeated applications (Fig. 6). To determine the rate of recovery from desensitization, 2-s puffs of 3,5-DHPG were repetitively applied at varying time intervals to neurons loaded with calcium green. The time course of recovery from desensitization was determined by plotting the amplitude of the current and calcium green fluorescence, expressed as the fraction of a preceding undesensitized control response, against the time interval between the two applications (Fig. 6B). Both these functions could be reasonably well described by single time constants of 67.4 ± 4.4 s and 28.6 ± 2.7 s. These time constants, as well as the amount of recovery from desensitization at 15-, 30-, and 60-s intervals, differed significantly between these two mGluR1-induced responses, with the [Ca2+]i signal showing a much faster recovery from desensitization. However, it might be possible that there is a nonlinear relationship between the dye response and free [Ca2+]i.
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Ca2+ signal results from mobilization of Ca2+ ions from intracellular stores, and the inward current is resistant to depletion of intracellular stores and persists in the absence of [Ca2+]i elevations
The 3,5-DHPG-induced elevation of
[Ca2+]i could be due to
an influx of Ca2+, for instance if the associated
inward current was carried at least in part by
Ca2+, or could result from a mobilization of
Ca2+ from intracellular stores. To determine the
source of the [Ca2+]i
elevations, responses induced by 3,5-DHPG were recorded first under
control conditions and then after switching to a
Ca2+-free and 1 mM EGTA containing extracellular
solution. Influx of calcium during depolarization of the cell to 30
mV for 30 s was used to monitor the wash out of extracellular
calcium. About 5 min after switching to the
Ca2+-free/EGTA extracellular solution, the first
application of 3,5-DHPG induced only a reduced calcium response while
subsequent agonist applications failed to elevate
[Ca2+]i, as well as did
depolarization of the membrane (Fig. 7).
In the absence of 1) extracellular calcium and 2)
intracellular calcium transients, the agonist-induced inward currents
persisted and amounted 177.1 ± 16.9% of controls
(n = 6). After returning to control medium, 3,5-DHPG
induced calcium elevations and inward currents that were not different
from those obtained before washing out Ca2+. As a
complementary approach we also added thapsigargin to the extracellular
solution to study the effect of abolition of the calcium elevations on
the inward currents. After wash in of thapsigargin, 3,5-DHPG-induced
calcium elevations were depressed, while the agonist induced inward
currents persisted (139.0 ± 1.09% of controls, n = 2; Fig. 8A). Also in slices
preincubated with thapsigargin (1 µM, 30-90 min) 3,5-DHPG-induced
inward currents could still be recorded while the
[Ca2+]i elevations were
reduced to 15 ± 7.4% of control (n = 4, Fig. 8B).
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DISCUSSION |
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In the present work we examined the relationship between the
response mediated by mGluR1 and changes in
[Ca2+]i and
[Na+]i in dopamine
neurons of the rat substantia nigra pars compacta. An inward current
mediated by group I mGluRs that requires the presence of extracellular
Na+ has been already described in these dopamine
neurons (Mercuri et al. 1993) as well as in several
other types of neurons (see INTRODUCTION). Here we
characterized for the first time the accompanying changes in both
[Ca2+]i and
[Na+]i, parameters that
provide new and direct evidence to the mechanism underlying this
current. In analogy with observations made in other types of neurons,
it is conceivable that the inward current in dopamine neurons is mainly
sodium dependent and mediated by a cation conductance with high
selectivity for Na+ (Congar et al.
1997
; Crepel et al. 1994
; Guerineau et
al. 1995
; Raggenbass et al. 1997
) or by an
electrogenic Na+/Ca2+
exchange (Lee and Boden 1997
; Linden et al.
1994
; Staub et al. 1992
). The observation that
the DHPG-induced inward current (see also Mercuri et al.
1993
) and the increase in
[Na+]i are not affected
either by a cocktail of CNQX and D-APV nor by TTX, rule out
the possibility that these responses are due to the activation of
excitatory amino acid ionotropic receptors and/or the
depolarization of unclamped dendrites. The fact that the inward current
is associated with an increase in [Na+]i and
neither requires a [Ca2+]i elevation nor the
presence of calcium ions in the extracellular environment favors the
involvement of a calcium-independent sodium-mediated conductance,
rather than the activation of a calcium-activated cation channels or
the sodium-calcium exchanger. As described previously (Mercuri
et al. 1993
), the mGluR-mediated current either caused a
parallel inward shift of the current-to-voltage relationship, or had an
extrapolated reversal potential above 0 mV. The parallel shift of the
current-to-voltage relationship could be explained if, in addition to
activation of a sodium conductance, a potassium conductance was changed
during activation of mGluR1 in dopamine cells (Shen and Johnson
1997
). Accordingly, we consistently observed that in the
absence of [Ca2+]i elevations (e.g., in
Ca2+-free/EGTA or thapsigargin-containing extracellular
solution; Figs. 7 and 8A), the 3,5-DHPG-induced inward
current was larger than in control conditions. One explanation for
these observations would be a contribution of a calcium-activated
K+ conductance to the mGluR-induced conductance changes
(Fiorillo and Williams 1998
).
Group I mGluRs, which involves the subtypes mGluR1 and mGluR5, are
known to couple to phosphoinositide hydrolysis and to induce mobilization of calcium from intracellular stores. Although this signal
transduction pathway was primarily established in recombinant cells, it
has also been identified in neuronal cells (Irving et al.
1992; Linden et al. 1994
; Netzeband et
al. 1997
; Vranesic et al. 1991
). Particularly,
it has been suggested that mGluR5 couples more efficiently to
phosphoinositide hydrolysis than does mGluR1 (Casabona et al.
1997
). In agreement with the study mentioned above, we observed
a rapid increase of [Ca2+]i during the
activation group I mGluRs, which is associated with the fast phase of
the inward current. The data obtained with the Ca2+-free/EGTA or thapsigargin-containing extracellular
solution definitely demonstrate that the elevation of intracellular
calcium is due to mobilization of calcium from intracellular stores and
that calcium is neither required as an activator nor as the main charge carrier for the inward current. Thus it appears that mGluR1 efficiently couples to an effector system that is independent from the
phospholipase C/Ca2+-signaling pathway in these cells.
The observation that CPCCOEt was more potent than S-MCPG in
antagonizing the 3,5-DHPG-induced current is in accordance with a
mGluR1-mediated effect (Batchelor et al. 1997;
Litschig et al. 1999
). Although both mGluRs antagonists
were more effective in blocking the inward current than the signal
transduction pathway associated with [Ca2+]i
elevation, the pharmacological profile of
[Ca2+]i elevation (more sensitivity to
CPCCOEt than to S-MCPG) also suggests a mediation by mGluR1 rather than
mGluR5. These findings are consistent with the prominent expression of
mGluR1 in dopamine cells (Kosinski et al. 1998
;
Testa et al. 1994
).
The 3,5-DHPG-induced inward current as well as the associated increase
in [Ca2+]i exhibited a marked reduction on
repeated applications that was rapid in onset and recovery. Responses
mediated by mGluR5 desensitize due to receptor autophosphorylation, but
this phenomenon appears to be absent in mGluR1 (Kawabata et al.
1996). The fact that the [Ca2+] i
responses were reduced after repeated agonist applications at short
intervals can be sufficiently explained by a depletion of intracellular
Ca2+ stores. The rapid recovery from the ability to produce
full-size [Ca2+]i signals would then
correspond to a rapid refilling of the intracellular Ca2+
stores. Most of the properties of the 3,5-DHPG-induced inward current
in dopamine cells are reminiscent of the cationic current described in
hippocampal CA3 pyramidal cells (Guerineau et al. 1995
).
In fact, this current appears to be activated by metabotropic receptors
via calcium-independent transduction process and shows desensitization
with a complete recovery from desensitization within a few minutes.
Recently, it has been described that a tetanic stimulation induces slow
mGluR-mediated excitatory or inhibitory synaptic potentials in dopamine
neurons (Fiorillo and Williams 1998; Shen and
Johnson 1997
). Thus it is conceivable that the inward current
described here might be the one generating the slow excitatory synaptic potentials.
Physiological implications
The scenario caused by the activation of group I mGluRs in the
ventral mesencephalon is certainly complex and appears to operate at
presynaptic and postsynaptic levels on the dopaminergic neurons. This
comprehends the inhibitory response described by Fiorillo and
Williams (1998), the excitatory response described by
Mercuri et al. (1993)
and Shen and Johnson
(1997)
, and the presynaptic inhibition of transmitter release
described by Bonci et al. (1997)
and Wigmore and
Lacey (1998)
.
Thus it might be speculated that discrete glutamatergic inputs to distinct zones of the dopamine cells might induce an inhibitory metabotropic response while more diffuse inputs driven at a higher frequency might mainly induce an excitatory metabotropic response. This phenomenon would ultimately change the functional significance of the synaptic inputs to the dopamine cells and consequently the state of their output in the terminal fields.
In a pathological context a dysfunction of the mGluR1-mediated inward
current might alter the activity of the dopaminergic system in
psychiatric disorders and participate to the excitotoxic neurodegeneration underlying Parkinson's disease (Albin and
Greenamyre 1992;Carlsson and Carlsson 1990
).
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ACKNOWLEDGMENTS |
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We thank G. Gattoni and M. Federici for technical assistance.
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FOOTNOTES |
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Address for reprint requests: N. B. Mercuri, Experimental Neurology Laboratory, IRCCS S. Lucia, 00179 Rome, Italy.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 22 October 1998; accepted in final form 22 April 1999.
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REFERENCES |
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