Protective role of neuronal KATP channels in brain hypoxia
Department of Physiology & Pediatrics, Perinatal Research Centre, University of Alberta, 232 HMRC, Edmonton, Alberta, T6G 2S2, Canada
e-mail: klaus.ballanyi{at}ualberta.ca
Accepted 20 May 2004
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Summary |
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Key words: anoxia, ATP-sensitive K+ channels, brainstem, calcium, fura-2, mitochondria
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Introduction |
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In a variety of central mammalian neurons, the terminal anoxic
depolarisation is preceded by a K+ channel-mediated
hyperpolarisation (Misgeld and Frotscher,
1982; Hansen,
1985
; Haddad and Jiang,
1993
). This hyperpolarisation reduces neuronal activity, and thus
transmembrane ion fluxes, and consequently attenuates the activity of ion
pumps that consume about 50% of the energy supplied to the brain
(Hansen, 1985
;
Hochachka, 1986
). Accordingly,
if the anoxic hyperpolarisation persists for a reasonable length of time, it
may well have a protective effect. The cellular mechanisms leading to
activation of the anoxic K+ conductance are still under discussion.
Several reports on hippocampal neurons indicated that the anoxic
Cai rise promotes activation of Ca2+-dependent
K+ channels (Leblond and
Krnjevic, 1989
; Nowicky and
Duchen, 1998
; for further references, see
Kulik et al., 2002
). But, an
increasing number of studies provides evidence that ATP-sensitive
K+ (KATP) channels mediate the anoxic hyperpolarisation
(Mourre et al., 1989
;
Luhmann and Heinemann, 1992
;
for further references, see Kulik et al.,
2002
). The pharmacological and biophysical properties as well as
the structure of KATP channels have been investigated thoroughly in
muscle tissues and pancreatic ß-cells
(Ashcroft and Gribble, 1998
;
Aguilar-Bryan and Bryan, 1999
).
By contrast, the structurefunction relationship of the neuronal
isoforms of these metabolism-regulated K+ channels has only
recently been explored using molecular techniques such as in situ
hybridisation or polymerase chain reaction (PCR) combined with patch-clamp
recording (Karschin et al.,
1998
; Liss et al.,
1999
; Zawar and Neumcke,
2000
; Haller et al.,
2001
). Although agents such as tolbutamide or glibenclamide block
the anoxic activation of neuronal KATP channels, it has only been
shown in a few cases that blockade of KATP channels by such
sulfonylureas increases the vulnerability of neuronal structures to anoxia
(Pek-Scott and Lutz, 1998
;
Garcia de Arriba et al.,
1999
).
In this review, the latter aspect is addressed for three neuronal systems (Fig. 1). Patch-clamp recording was combined with fluorometric measurements of Cai to determine whether KATP channels are involved in the response to oxygen depletion of dorsal vagal neurons and Purkinje cells in brain slices from mature rodents. The potential for KATP channels to contribute to the anoxic slowing of respiratory frequency in neonatal rats was also investigated. For this purpose, the response to anoxia of the respiratory network in isolated brainstems of newborn rats was studied using nerve recordings of respiratory activity combined with `blind' patch-clamp recordings.
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KATP channels in anoxia-tolerant dorsal vagal neurons |
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The view that KATP channels are responsible for the anoxic
hyperpolarisation is supported by results from single-channel studies. The
single-channel conductance is 70 pS in both cell-attached
(Fig. 2B,C;
Karschin et al., 1998) and
excised inside-out patches, the latter obtained from dorsal vagal neurons of
mice (Fig. 2D;
Müller et al., 2002
).
This value, and also the half-maximal inhibitory concentration
(IC50) for blocking channel activity by intracellular ATP, 5
µmol l1 (Müller
et al., 2002
), resembles closely that described for
KATP channels in pancreatic ß-cells
(Ashcroft and Gribble, 1998
;
Aguilar-Bryan and Bryan, 1999
).
Consequently, single-cell aRNA-PCR analysis revealed that dorsal vagal neurons
coexpress mRNA for the ß-cell type sulfonylurea receptor (SUR) isoform,
SUR1, and for the inwardly rectifying K+ (Kir) channel
subunit, Kir6.2 (Fig.
2E; Karschin et al.,
1998
). These findings established that KATP channels
mediate the persistent anoxic hyperpolarisation of dorsal vagal neurons.
Despite this, it is necessary to test whether activation of
Ca2+-dependent K+ channels may contribute, at least in
part, to the anoxic hyperpolarisation. A molecular analysis demonstrated that
the apamin-sensitive SK1 isoform of `small conductance'
Ca2+-dependent K+ channels and the `big conductance',
iberiotoxin- and tetraethylammonium-sensitive BK
-subunit are expressed
in dorsal vagal neurons (Pedarzani et al.,
2000
). However, the SK1-mediated current is blocked by anoxia
while the BK current is not changed (Kulik
et al., 2002
). For some neuronal systems, it appears that
accumulation of interstitial adenosine due to anoxic degradation of ATP acts
via A1 receptors on K+ channels, possibly
including KATP channels, to exert a protective role by suppressing
electrical activity (Pek-Scott and Lutz,
1998
; Mironov et al.,
1999
; Mironov and Richter,
2000
). However, in dorsal vagal neurons, adenosine does not mimic
the hyperpolarising effect of anoxia while the anoxic hyperpolarisation is not
blocked by the A1 receptor antagonist DPCPX
(Ballanyi and Kulik, 1998
).
The extent to which anoxia elevates Cai was studied in dorsal
vagal neurons filled via the patch-electrode with the
Ca2+-sensitive dye fura-2. 20-min periods of (chemical) anoxia
only evoke a very moderate (<100 nmol l1) and stable rise
of Cai (Fig. 3A;
Ballanyi and Kulik, 1998
;
Kulik et al., 2000
). As the
anoxic rise of Cai is not affected by removal of extracellular
Ca2+, it must be due to release from intracellular stores
(Fig. 3B). The Cai
rise related to (chemical) anoxia is also not affected by depleting
endoplasmic reticulum Ca2+ stores with cyclopiazonic acid
(Fig. 3C). On the contrary, the
Cai response to anoxia or cyanide is both mimicked and occluded by
the protonophore FCCP (Fig.
3C), which dissipates the mitochondrial transmembrane
H+ gradient (Schuchmann et al.,
2000
). These results suggest that the moderate anoxic rise of
Cai is caused by mitochondrial Ca2+ release
(Kulik and Ballanyi,
1998
).
This view is supported by observations in dorsal vagal neurons filled
via the patch-electrode with fura-2 and the mitochondrial
potential-sensitive dye rhodamine-123 together
(Fig. 3D). These results showed
that the kinetics of the cyanide-induced KATP current closely
correlate with those of a rapid and pronounced increase in rhodamine-123
fluorescence, indicating a major depolarisation of mitochondrial potential,
while the accompanying Cai rise has considerably slower kinetics
(Fig. 3D). By contrast, a major
rise of Cai in response to membrane depolarisation in voltage-clamp
is only reflected by a minor mitochondrial depolarisation
(Fig. 3D;
Kulik and Ballanyi, 1998).
The very similar time courses of the anoxic outward current and the
mitochondrial depolarisation suggest that metabolic activation of
KATP channels is due to a rapid cellular process associated with
loss of the mitochondrial membrane potential. The nature of this process is
currently under investigation. A change in the redox state of the
KATP channels is unlikely to be involved as neither
reduced/oxidised glutathione nor the oxidase blocker diphenyliodonium has an
effect on the cyanide-induced outward current
(Müller et al., 2002).
Also, an anoxia-related change in the actin cytoskeleton or the composition of
the plasma membrane does not seem to have a major contribution as
cytochalasin-D does not affect the cyanide-induced hyperpolarisation and
phosphatidyl-inositol 4,5-bisphosphate fails to decrease the ATP sensitivity
of single KATP channels
(Müller et al., 2002
).
The same study also suggests no major role for ATP in anoxic activation of
dorsal vagal neuronal KATP channels, as dialysing the cells
via the patch-electrode with either 0, 1 or 20 mmol
l1 ATP does not affect the amplitude or delay of onset of
the cyanide-induced outward current. Furthermore, the current peaks within 1
min, independent of whether or not the cells are exposed to ouabain and
vanadate that block the ion pumps that constitute the major source of ATP
consumption (Müller et al.,
2002
). Finally, the fall of intracellular pH of up to 0.5 units
that accompanies the modest rise of Cai does not appear to
contribute to anoxic activation of KATP channels. In most cells,
the intracellular acidosis starts to develop after the outward current reaches
its maximum amplitude (Trapp et al.,
1996
; Raupach and Ballanyi,
2004
).
The KATP channels of dorsal vagal neurons do not seem to play a
protective role during anoxia. Upon sustained exposure to hypoxic or chemical
anoxia, the rise of Cai b100 nmol l1 is less
than doubled upon sulfonylurea-induced block of the KATP
channel-mediated hyperpolarisation or outward current
(Fig. 3A; Ballanyi and Kulik, 1998
). The
additional moderate Cai increase is related to reappearance of
tonic spiking that is typical for these cells and promotes a notable influx of
Ca2+ (Ballanyi and Kulik,
1998
). A progressive depolarisation or rise of Cai is
not observed as in anoxia-vulnerable cells (see below)
(Hansen, 1985
;
Haddad and Jiang, 1993
;
Kristian and Siesjö,
1996
; Lipton,
1999
). This is certainly not due to the fact that the cells were
whole-cell recorded with patch-electrodes containing 12 mmol
l1 ATP. A similar lack of occurrence of a terminal
depolarisation or massive Cai increase is observed when the dorsal
vagal neurons are recorded with sharp microelectrodes
(Cowan and Martin, 1992
;
Ballanyi et al., 1996a
) or
optically in a non-invasive manner using a membrane-permeable form of fura-2
(Ballanyi and Kulik, 1998
).
According to these results, it is proposed that the tolerance to anoxia of
these mammalian neurons is rather due to a low resting metabolic rate in
conjunction with effective utilisation of anaerobic metabolism
(Ballanyi et al., 1996a
;
Trapp et al., 1996
;
Ballanyi and Kulik, 1998
).
Which alternative function might these KATP channels have? Since
the dorsal vagal neurons innervate several organs of the gastrointestinal
tract, their metabolism-gated K+ channels may be involved in
nutritive functions. Accordingly, stimulation of the dorsal vagal nucleus
in vivo results in a substantial release of insulin as a
subpopulation of dorsal vagal neurons innervates pancreatic ß-cells
(Laughton and Powley, 1987).
In line with a putative role in glucose homeostasis, the KATP
channels of the dorsal vagal neurons are not only activated by anoxia but also
by a fall of interstitial glucose levels
(Ballanyi et al., 1996a
). Thus,
these neuronal KATP channels may represent a central nervous
glucose sensor such as in hypothalamic neurons
(Miki et al., 2001
). However,
the sensor mechanism may be different as the KATP channels of
hypothalamic neurons respond within much shorter time periods to a fall of
interstitial glucose levels (Miki et al.,
2001
).
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KATP channel-mediated delay of anoxic Cai rise in Purkinje neurons |
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Analysis of the spatiotemporal pattern of the anoxic rise of Cai using digital CCD camera imaging revealed that levels of Cai are very similar in somatic and dendritic regions of the Purkinje cells at rest. As shown in Fig. 5, application of cyanide for 5 min in the presence of tolbutamide induces first a comparable moderate Cai rise in both the soma and dendrites. After about 1 min, a major rise of Cai develops in the distal dendrites and proceeds within the following 90 s towards the soma until a similar elevation of Cai is seen in both. Upon washout of cyanide, Cai recovers first in the soma and then in the dendrites.
|
These findings suggest that anoxia promotes initially a moderate rise of
Cai, possibly due to release from intracellular (mitochondrial)
stores as suggested above for the dorsal vagal neurons. In contrast to the
anoxia-tolerant dorsal vagal cells, the vulnerable Purkinje neurons are
subjected to a secondary progressive Cai rise that is irreversible
in a major population of cells when cyanide or hypoxic anoxia are applied for
several minutes, particularly in the presence of tolbutamide. The secondary
cyanide-induced rise of Cai appears to be related to membrane
depolarisation, as it develops more rapidly when the anoxic hyperpolarisation
is suppressed with sulfonylurea KATP channel blockers. Similarly,
dialysing the cells with a mixture of Cs+ and TEA+
reveals an immediate onset of the progressive anoxic Cai rise with
no occurrence of a cyanide-induced outward current
(Fig. 4C,D). The latter
prominent rises of Cai are not affected by a mixture of
6-cyano-7-nitroquino-xaline-2,3-dione and 2-amino-5-phosphonovalerate to block
ionotropic glutamate receptors (Fig.
4C; for references, see Kulik
et al., 2000) while they are abolished by Ca2+-free
superfusate or extracellular Cd2+
(Fig. 4D). The lack of effects
of glutamate receptor blockers on the progressive Cai rise and the
potency of Cd2+ and Ca2+-free superfusate to suppress
this response indicates, on the one hand, that anoxia affects the
activationinactivation characteristics of voltage-gated Ca2+
channels in these cells as shown for other types of mammalian neurons
(Sun and Reis, 1994
;
Brown et al., 2001
;
Lukyanetz et al., 2003
). On
the other hand, it is obvious that KATP channels counteract, at
least during the time course of several minutes, the secondary massive rise of
Cai and thus have a protective role during short periods of anoxia
in these vulnerable mammalian neurons.
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KATP channel-mediated anoxic slowing of breathing in newborn rats |
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A series of reports on the latter preparation (Ballanyi et al.,
1992,
1994
,
1999
;
Brockhaus et al., 1993
;
Voipio and Ballanyi, 1997
;
Ballanyi, 2004
) has led to the
view that the high tolerance of the respiratory network in newborn mammals to
oxygen depletion includes two cooperative processes. On the one hand, anoxia
appears to effectively stimulate anaerobic glycolysis (`Pasteur effect';
Lutz and Nilsson, 1994
;
Hochachka and Lutz, 2001
). In
agreement with the efficacy of the Pasteur effect, up to 50% of the ATP
production under normoxic conditions in neonates appears to be due to
anaerobic metabolism, in contrast to <20% in adults
(Hansen, 1985
). Accordingly, a
high lactate dehydrogenase activity supports the notion of an important role
of anaerobic glycolysis during the perinatal period
(Booth et al., 1980
). By
contrast, the activity of cytochrome c oxidase (an indicator of
oxidative glucose utilisation) increases only after P1217
(Wong-Riley, 1989
). Due to the
low efficacy of anaerobic ATP production, survival of neurons during extended
periods of anoxia is only possible as the metabolic rate of neonatal brain
tissue is very low, i.e. in postnatal day-1 rats <5% of that in adults
(Duffy et al., 1975
;
Hansen, 1985
). Thus, in the
perinatal period, cerebral glucose consumption appears to be <10% of that
in adult rats (Vannucci and Vannucci,
1978
). Despite a reduced in vitro temperature
(2528°C), the metabolic rate is not extremely low in the
brainstemspinal cord preparation of newborn rats as the glycolytic
blocker iodoacetate or removal of glucose from the superfusate profoundly
perturbs both the respiratory rhythm and ion homeostasis within the
respiratory network within 30 min (Ballanyi et al.,
1996b
,
1999
). These effects are
accompanied by a progressive depolarisation of neonatal respiratory neurons
often preceded by a hyperpolarisation lasting between 2 and 4 min
(Ballanyi et al., 1999
).
The second process contributing to the anoxia tolerance of the neonatal
respiratory network is constituted by downregulation of metabolic rate and
demand by `functional inactivation' of ion conductances as described for
cold-blooded vertebrates (Hochachka and
Lutz, 2001). Most (>60%) of the respiratory neurons in neonatal
rats in vitro respond with a sustained K+ channel-mediated
hyperpolarisation and conductance increase in response to blockade of aerobic
metabolism by either anoxia or cyanide (Figs
6B,C,
7C; Ballanyi et al.,
1994
,
1999
). In about 50% of these
cells, the anoxic hyperpolarisation coincides with suppression of
respiratory-related membrane potential fluctuations
(Fig. 6C). This is particularly
obvious in pre-inspiratory neurons that appear to constitute a second
respiratory centre in addition to the PBC
(Ballanyi et al., 1999
). More
than 90% of these cells are hyperpolarized and inactivated during anoxia,
while a subpopulation of these VRG cells receives burst-type subthreshold
synaptic inputs that are not in phase with the slowed inspiratory motor output
(Fig. 7C). Such anoxic
functional inactivation of a major portion of respiratory neurons does not
reflect a pathophysiological impairment of synaptic transmission or membrane
excitability. Action potentials can still be evoked in these cells while drive
potentials of a different subpopulation of inspiratory VRG neurons remain
vitually unaltered by anoxia (Fig.
6B; Ballanyi et al.,
1994
,
1999
;
Ballanyi, 2004
). This tolerance
to anoxia of excitatory synaptic transmission in a subclass of neonatal
respiratory neurons coincides with the ability of inspiratory premotoneurons
and motoneurons to generate (respiratory-related) spiking as obvious from the
persistence of inspiratory motor output during anoxia.
For some neuronal tissues, evidence has been presented that adenosine
formed during anoxia may act via A1 receptors on
KATP or other K+ channels to exert a protective function
(Pek-Scott and Lutz, 1998;
Mironov and Richter, 2000
).
However, the effects of adenosine on the respiratory network are not yet
clear. The agent strongly depresses breathing in vivo and this is
antagonised by aminophylline, i.e. theophylline
(Hedner et al., 1982
;
Eldridge et al., 1985
). On the
other hand, adenosine stimulates breathing in conscious, unanesthetised humans
(Fuller et al., 1987
;
Griffith et al., 1997
). The
depressant effect of adenosine on breathing in vivo is more potent
during the time period around birth and/or is also more severe in anesthetised
animals (Herlenius et al.,
2002
). Hypoxiaanoxia elevates adenosine levels in the VRG
of adult cats in vivo (Richter et
al., 1999
) and in the rostral brainstem of fetal sheep
(Koos et al., 1994
). The
rostral brainstem has a high density of A1 adenosine receptors
(Bissonnette and Reddington,
1991
) that are possibly involved in central respiratory inhibition
in vitro and in vivo
(Herlenius and Lagercrantz,
1999
; Mironov et al.,
1999
). Furthermore, the adenosine receptor antagonist theophylline
blocks, at least partly, the depressant response to oxygen deprivation in
vivo (Darnall, 1985
). A
similar antagonistic effect of theophylline (165 µmol l1)
was revealed in the brainstemspinal cord preparation of newborn rats
(Kawai et al., 1995
). By
contrast, 500 µmol l1 theophylline or 2.5 µmol
l1 of the A1 adenosine receptor blocker
8-cyclopentyl-1,3-dipropylxanthine fails to reverse both the anoxic frequency
decrease and the hyperpolarisation of respiratory neurons in the same in
vitro preparation (Ballanyi et al.,
1999
). 8-cyclopentyl-1,3-dipropylxanthine is effective in
vitro as it blocks adenosine-mediated suppression of non-respiratory
excitatory postsynaptic potentials in VRG neurons and abolishes the
anticonvulsant effect of adenosine on spinal motor circuits
(Brockhaus and Ballanyi,
2000
). Finally, adenosine neither mimics the anoxic slowing of the
neonatal respiratory rhythm nor the concomitant hyperpolarisation of VRG
neurons (Fig. 7C).
According to the proposed pivotal role of PBC conditional burster neurons
in respiratory rhythm generation, an anoxic hyperpolarisation of these cells
and/or of cells that provide a tonic excitatory drive to these neurons would
slow the respiratory rhythm. Thus, it is possible that the K+
channel-mediated anoxic hyperpolarisation, observed in the majority of
neonatal respiratory neurons (Ballanyi et al.,
1994,
1999
;
Ballanyi, 2004
), is causally
related to the secondary respiratory depression. In line with this view,
Ba2+, which blocks inwardly rectifying K+ channels
including KATP channels
(Ashcroft and Gribble, 1998
;
Töpert et al., 1998
;
Aguilar-Bryan and Bryan, 1999
),
antagonises not only the anoxic hyperpolarisation of neonatal VRG cells
(Fig. 6C) but also the
accompanying frequency depression of respiratory rhythm
(Ballanyi et al., 1999
;
Ballanyi, 2004
). The same
reports provide more direct evidence for an involvement of KATP
channels, as both tolbutamide and the more potent sulfonylurea gliclazide
reverse both the depressing effect of anoxia on respiratory frequency
(Fig. 7A) and the anoxic
hyperpolarisation or outward current of VRG neurons
(Fig. 7B)
(Ballanyi et al., 1999
;
Ballanyi, 2004
; see also
Haller et al., 2001
;
Mironov and Richter,
2000
).
This raises the question of whether the cellular ATP concentration
decreases considerably in neonatal respiratory neurons during anoxia. The
above findings in medullary dorsal vagal neurons suggest that anoxic
activation of neuronal KATP channels occurs in the absence of a
major fall in ATP concentrations
(Müller et al., 2002).
Furthermore, cellular ATP levels do not appear to decrease profoundly in the
neonatal respiratory network during anoxia periods of up to 30 min
(Duffy et al., 1975
;
Wilken et al., 1998
). In
addition to Ba2+ and tolbutamide, muscarine and
thyrotropin-releasing hormone reverse the respiratory response to anoxia in
the brainstemspinal cord preparation
(Ballanyi et al., 1999
;
Ballanyi, 2004
). This suggests
that a yet undetermined mediator acting on (G protein-regulated)
KATP channels is released (or suppressed) during anoxia.
Alternatively, cellular processes such as changes in phosphorylation or redox
state may be responsible for KATP channel activation and, thus, for
anoxic slowing of rhythm, although these processes do not appear to contribute
to activation of the KATP channels in dorsal vagal neurons
(Müller et al., 2002
).
The observation that the anoxic slowing of the neonatal respiratory rhythm is
mediated by KATP channels shows that this is not a pathological
consequence of anoxic perturbation of cellular function. Rather, it may
represent an adaptive mechanism serving for conservation of energy during
severe hypoxia such as that occurring during birth
(Ballanyi, 2004
).
Interestingly, KATP channels appear to be active during normoxia,
as sulfonylureas depolarise dorsal vagal neurons of medullary slices
(Trapp et al., 1994
) as well
as respiratory neurons in vivo
(Pierrefiche et al., 1998
) and
in vitro (Haller et al.,
2001
). That the physiological activity of KATP channels
is relevant for respiratory functions is indicated by the observation that
sulfonylureas increase the frequency of the respiratory rhythm in medullary
slices from newborn rats (K. Ballanyi and L. Secchia-Ballanyi, unpublished
observations).
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Conclusions |
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Acknowledgments |
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