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Glial calcium and sodium signalling
How calcium signalling was discovered
Principles of calcium signalling
Calcium signalling in neuroglia
Voltage- and ligand-gated channelsEndoplasmic reticulum calcium storeStore-operated calcium entryCalcium signals in neuronal-glialinteractionsGlial calcium waves
Comcept of Na+ signalling
1
Professor Hamphry Davy(1778-1829)
The scientific story of calcium began in1808, when Sir Humphry Davy was able toshow that lime (which had hitherto beenconsidered to be an inseparable element)was actually a combination of metal andoxygen (hence Calcium - from Latin Calxfor chalk).Sir Humphry tried to purify calcium byexposing a mixture of lime and mercuricacid to electric current; he succeeded inobtaining an amalgam of calcium, butfurther separation of mercury was sodifficult that even Davy himself was notcertain of whether he had obtained puremetallic calcium. In fact, he nevermanaged to isolate this new metal in a pureform, and metallic calcium remained alaboratory curiosity for another 50 years,until Henry Moissan obtained 99% purecalcium by electrolysing calcium iodide.
Calcium - the beginning 2
Calcium signalling: The BeginningThe creator of calcium signalling
Sydney Ringer found that Ca2+ is crucially important for
- survival of fish Ringer S. (1883) The influence of saline media on fishes. J. Physiol. Lond., 4, vi-viii.
- the contraction of the heart and skeletal muscle Ringer S. (1883) A further contribution regarding the influence of different constituents of the blood on the contractions of the heart. J. Physiol. Lond., 4, 29-43.Ringer S. (1886) Further experiments regarding the influence of small quantituies of lime, potassium and other salts on musclular tissue. J. Physiol. Lond., 7, 291-308. Ringer S, Buxton LW. (1887) Concerning the action of calcium, potassium and sodium salts upon the eel's heart and upon skeletal muscles of the frog. J. Physiol. Lond., 8, 15 - 19.
- fertilisation of eggs and development of the tadpoleRinger S, Sainsbury H. (1894) The action of potassium, sodium and calcium salts on Tubifex rivulorum. J. Physiol. Lond., 16, 1-9
Several years later Locke and Overton found that Ca2+ is critical for impulse transmission between nerve and muscle.
Locke FS. (1894) Notiz uber den Einfluss, physiologisher Kochsalzlosung auf die Eregbarkeit von Muscel and Nerve. Zentralbl. Physiol., 8, 166-167.Overton E. (1904) Beitrage zur allgemeinen Muskel- und Nerven physiologie. III. Mittheilung. Studien uber die Wirkung der Alkali- und Erdkali-salze auf Skeletalmuskeln und Nerven. Pflugers Arch., 105, 176-290
3 Calcium chloride added to distilled water sustains life muchlonger than either corresponding quantities of sodium orpotassium salts. For instance, with 30 cc of 1 per cent.solution of calcium chloride to the 1000 c.c. of distilled water,six fish died on average in 47 hours; whilst nine werestill alive on the 12th day.
Ringer, S., 1883,The influence of saline media on fishes,J. Physiol. Lond. 4, vi-viii.
4
Calcium signalling – the idea is born
Lewis Victor Heilbrunn1892-1959 "The sensitivity of protoplasm and its response to
stimulation are believed to be due to a sensitivityto free calcium ion and it is believed that thefreeing of calcium and the reaction of this calciumwith the protoplasm inside the cell is the mostbasic of all protoplasmic reactions.“
An Outline of General Physiology (1943 – 1952)
2. Typically (and perhaps always) the outer part of the protoplasm consistsof a rigid cortex.…7. When a cell is exposed to stimuli, such as heat, cold, mechanical impact,electric shock, ultraviolet radiation, etc., the cortex is liquefied andcalcium is released from the cortex into the cell interior.
The Dynamics of Living Protoplasm (1956)
5 Calcium signalling - Early discoveries
1947: Heilbrunn and Wiercinski observed rapid and strong contractions after directly injecting minute amounts of Ca2+ into muscle fibres Heilbrunn LV, Wiercinsky FJ. (1947) Action of various cations on muscle protoplasm. J. Cell. Comp. Physiol., 19, 15 - 32.
1948 - 1954: Schwarzenbach and Ackerman synthesized EDTA Schwarzenbach, v. G. & Ackermann, H. (1954) Helv. Chim. Acta, 30, 1798 - 1804.
1954: Bozler found that the removal of Ca2+ by EDTA relaxed muscle fibers.Bozler E. (1954) Relaxation in extracted muscle fibers. J. Gen. Physiol., 38, 149 -159.
1959: Anne-Marie Weber discovered that Ca2+ ions after binding to myofibrils activate actomyosinWeber A. (1959) On the role of calcium in the activity of adenosine 5'-triphosphate hydrolysis by actomyosin. J. Biol. Chem., 234, 2764 - 2769.
6
Calcium signalling - Early discoveries
In the 1950s, Setsuro Ebashi, working under the guidance of ProfessorKumagai, found that in glycerol-extracted muscle, ATP could inducecontraction, which was not followed by relaxation, but subsequent addition of amuscle extract induced relaxation. Ebashi and his colleagues called this extractrelaxing factor [1]. This relaxing factor turned out to have characteristics incommon with a Mg2+-activated ATPase described earlier by Wayne Kielley andOtto Meyerhof [2]. In Fritz Lipmann’s laboratory, at the Rockefeller Institute inNew York, Ebashi was later able to demonstrate that the relaxing effect is dueto Ca2+ uptake into sarcoplasmic reticulum vesicles mediated by a Ca2+, Mg2+-activated ATPase [3]; similar results were obtained independently byHasselbach and Makinose [4].
This finding, although originally related specifically to muscle relaxation, is fundamental to ourunderstanding of Ca2+ signalling generally, since it introduced for the first time the concept of anintracellular membrane-bounded Ca2+ store. In 1968, Setsuro Ebashi and Makoto Endo [5] outlined thetheory of muscle contraction as we know it now. They wrote “Ca ion discharged from the sarcoplasmicreticulum under the influence of action potential affects troponin and releases the actin filament from itsdepressed state, resulting in contraction. The sarcoplasmic reticulum then removes Ca ion from troponin atthe expense of ATP and induces relaxation” [5].
Kumagai H, Ebashi S, Takeda F. (1955) Essential relaxing factor in muscle other than myokinase and creatine phosphokinase. Nature, 176, 166.Kielley WW, Meyerhof O. (1948) Studies on adenosintriphosphatase of muscle. II. A new magnesium-activated adenosinetriphosphatase. J. Biol. Chem., 176, 591-601.Ebashi S, Lipmann F. (1962) Adenosine triphophate-linked concentration of calcium ions in a particulate fraction of rabbit muscle. J. Cell. Biol., 14, 389 - 400.Hasselbach W, Makinose M. (1962) ATP and active transport. Biochem. Biophys. Res. Commun., 7, 132-6.Ebashi S, Endo M. (1968) Calcium ion and muscle contraction. Prog. Biophys. Mol. Biol., 18, 123-83.
Setsuro Ebashi
7 Patch-clamp and fluorescent Ca2+ indicators
Calcium probesPatch-ClampErwin Neher Bert Sakmann Roger Tsien
Neher E, Sakmann B. (1976) Single-channelcurrents recorded from membrane of denervatedfrog muscle fibres. Nature, 260, 799-802.Hamill OP, Marty A, Neher E, Sakmann B, SigworthFJ. (1981) Improved patch-clamp techniques forhigh-resolution current recording from cells andcell-free membrane patches. Pflugers Arch, 391,85-100.
Tsien RY. (1980) New calcium indicators andbuffers with high selectivity against magnesium andprotons: design, synthesis, and properties ofprototype structures. Biochemistry, 19, 2396-2404.Tsien RY. (1981) A non-disruptive technique forloading calcium buffers and indicators into cells.Nature, 290, 527-528.Grynkiewicz G, Poenie M, Tsien RY. (1985) A newgeneration of Ca2+ indicators with greatly improvedfluorescence properties. J Biol Chem, 260, 3440-3450.
8
Diversity and versatility of calcium probes
G
Voltage- and ligand-gated calcium channels
Metabotropic receptor
Ca2+
Ca2+
SERCA
InsP3
RyR InsP R3
PMCA
ATPADPH+
Ca2+
Na+
NCE
Leak channel(s)
Cytosolic Ca probes2+
ER Ca probes2+
Mitochoindrial Ca probes2+
9
ERcytosol
Mag-Fura-2
Fluo
-3
Fluo-3
cytosol Fura-2
Fura
-2
20 s
1.0
3.0
F/F
0[C
a](
M)
2+L
m
Caf Caf
1
2
3
4
5
170
80
1 2 3 200
2200
70
500
[Ca
](M
)2+
Lm
F488
(a.u
.)
Combination of patch- voltage-clamp with Ca2+ indicators
Kano M, Garaschuk O, Verkhratsky A & Konnerth A (1995)Journal of Physiology, London., 487, 1- 16
Solovyova N & Verkhratsky A (2002): J.Neurosci Meth, 21: 622-620
10
Calcium as universal signalling molecule
Fluctuations of extracellular [Ca2+]
From: Ward DT (2004)In: Cell Calcium special issue on “Calcium-sensing receptor: physiology, pathology and pharmacological modulation”Ed by D. Riccardi
Calcium as a hormone Calcium as multi-level intracellular messenger
Imm
edia
te e
ffect
sm
secc
onds
- se
cond
sD
ealy
ed e
ffect
sse
cond
s - m
oths
From: Verkhratsky A & Toescu EC (1998) Integrative aspects of calcium signalling, Plenum Press
11 Calcium signalling in neurones and neuroglia: general principles
Nedergaard, M., Rodriguez, JJ & Verkhratsky, A (2010): Cell Calcium v. 47, p. 140-149.
12
Calcium signalling provides the substrate for glial excitability
13 Glial calcium signalling: mechanisms of generation
1. Voltage-gated calcium channels
Glial cells are non-excitable cells in physiological sense (i.e. theycannot generate action potentials. Nonetheless glial cells express aseveral types of voltage-gated ion channels including voltage-gatedcalcium channels.
Voltage-gated Ca2+ channels are generally present in immature glialcells or in glial precursors and their expression is down-regulatedduring development.
14
-45
-35
-25
-15
-5
5
-40
20 40
-700
I m (p
A)
Vm(mV)
HP -75 mVHP -40 mV
250 pA100 ms
40
Calcium currents in glial cells
Immature astrocyte Oligodendrocyte precursor
Akopian, G, Kressin, K, Derouiche, A & Steinhauser, C, (1996): Glia, v. 17, p. 181-194.
Verkhratsky, AN, Trotter, J & Kettenmann, H, (1990): Neurosci Lett, v. 112, p. 194-198.
15
soma (a)
processes (b)
25 s
50 mM K+ 50 mM K+ + 50 μM Ni2+
2.2
F/F 0
2.2
F/F 0
B
1.0
1.0
F/F
0
50 s
A
Low-voltage-activated calcium channels are preferentiallylocalized in the tips of glial precursor cells processes
Kirischuk, S, Scherer, J, Moller, T, Verkhratsky, A & Kettenmann, H, (1995): Glia, v. 13, p. 1-12.
16
Glial calcium signalling: mechanisms of generation
2. Ligand-gated calcium channels
All types of neuroglial cells express ligand-gated ion channels,generally referred to as ionotropic receptors. The most abundant areglutamate receptors (of AMPA, Kainate and NMDA types) andpurinoceptors (or P2X receptors). Many of these channels arepermeable to Ca2+ and can generate cytosolic Ca2+ signals.
17
B C
kainate kainate
30 s0.25
30 s0.25
F 340/380F 340/380
kainate kainate
kainate
30 s100 pA 50 pA
30 s
Ca2+ -free
kainate + CNQXkainate
kainate + CNQX
A
F340/380
control kainate
Purkinje celllayer
Bergmannglial cell
patch pipette loadedwith fura-2
Kainate induces massive calcium influx mediated by AMPA receptors into Bergmann glial cell in cerebellar slice preparation
Verkhratsky, A, Orkand, RK & Kettenmann, H, (1998) : Physiol Rev, v. 78, 99-141.
18
Glial calcium signalling: mechanisms of generation
3. Endoplasmic reticulum provides a substrate for glial excitability
Ca2+ release following stimulation of metabotropic receptors and production ofInsP3 forms cytosolic Ca2+ signals, Ca2+ oscillations and propagating Ca2+
waves, which travel along single glial cell and between glial cells, thus allowingintegration within glial networks.
19
Ca2+
Na+
InsP3
InsP R3
InsP R3
RyR- ?
VGCCSOCC
SERCA
Ca - BP2+
ER
ATP
ADP
mGluR1
α1AR
α2AR
P2Y
MGluR5
P2U
P2T
A1
GABAB M1 M2 OXPAFR AT1ETB
5-HT2A
5-HT2C
V1
H1
NK1
B2ETA
Glutamate
Serotonin
Histamine
Substance P
Adrenaline
ATP
Adenosine
GABA Ach Endothelin VasopressinBradikinin Angiotensin IIPAFOxytocin
?
AMPA/KA
NMDA-?
P2X/2Z
GABAA
GLT
Na+
Na+
Ca2+
depolarization
Neurotransmitter receptors and InsP3-mediated Ca2+ signallingin glial cells
20
Visualisation of endoplasmic reticulum by fluorescent thapsigargin in cultured astrocytes
Verkhratsky, Solovyeva & Toescu (2002): In: Glia in synaptic transmission, Ed. by Volterra, Haydon & Magistretti, OUP, p. 91 - 109.
0
2
4
6
8
10
100 150 200 250 300
Num
ber o
f cel
ls
[Ca ] ( M)2+L μ
[Ca
] (
M)
2+Lμ
Ast
rocy
tes
DR
G
Hip
poca
mpa
l
Pur
kinj
e
Neurones
100
200
300
400
500
600
0
[Ca
] (
M)
2+Lu
μ
500
10
Resting Ca2+ concentration within the ER lumen in astroglia
Verkhratsky, Solovyeva & Toescu (2002): In: Glia in synaptic transmission, Ed. by Volterra, Haydon & Magistretti, OUP, p. 91 - 109.
21
M M
InsP
3R
1
InsP
3R
2
InsP
3R
3
100
300
600
astroglia oligodendroglia
InsP
3R
1
InsP
3R
2
InsP
3R
3
Expression of InsP3 receptors in glial cells
Kirchhoff & Verkhratsky, unpublished
22
A
B
0
200
400
600
800
1000
1200
1400
[Ca
] (n
M)
2+i
20 s
KCl90 mM 3 s
ATP/Ca-free100 M 5 sμ
ATP/Ca-free100 M 5 sμ
KCl90 mM 30 s
neuroneastrocyte
1 2
1 2
90 mM KCl 100 M ATP/Ca2+-freeμ
Calcium signalling in neurones and glia: Extracellular vs. intracellular pathway
Verkhratsky, Solovyeva & Toescu (2002): In: Glia in synaptic transmission, Ed. by Volterra, Haydon & Magistretti, OUP, p. 91 - 109.
23
[Ca2+
] i (nM
)
250
65 5 min
ATP
Ca2+-free
80
200
[Ca2+
] i (nM
)
A B
500 nM thapsigargin
30 s
5 min
ATP ATP ATPATPATP
30 s
[Ca2+
] i (nM
)
50
180
ATP
CControl
50 s
ATP
Heparin
25 s
D
>3
F/F
01
ATP triggers calcium release from InsP3-sensitive stores in Bergmann glial cells in cerebellar slices
Kirischuk, S, Moller, T, Voitenko, N, Kettenmann, H & Verkhratsky, A, (1995): J Neurosci, v. 15, p.7861-7871.
24
800 1000
X Axis Title
170
200 160
170
50
40 40
50
50 s
ATP, 100 Mμ ATP, 100 Mμ
InsP , 10 M3 μ
InsP , 10 M3 μ
ATP, 100 Mμ
ATP, 100 Mμ
[Ca
] (
M)
2+Lμ
[Ca
] (
M)
2+Lμ
[Ca
] (
M)
2+Lμ
[Ca
] (
M)
2+Lμ
TG, 5 Mμ
TG, 5 Mμ TG, 5 Mμ
100 s
InsP3 triggers Ca2+ efflux from astroglial endoplasmic reticulum
Solovyova & Verkhratsky, unpublished
25
NA
A
A10 mμ caf caf
InsP3
InsP3
TG
50 100 150
X Axis Title
caf
ATP
ATP
caf caf
650
70
[Ca
] (n
M)
2+i
20 s
180
50
[Ca
] (
M)
2+Lμ
A B
Astrocytes express ryanodine receptors, yet their function remains enigmatic
Solovyova & Verkhratsky, unpublished
26
F (a
.u.)
600
700
800
900
1000
[Ca
] (n
M)
2+i
[Ca ] ~ 200 M2+L μ
100
200
300
400
500
600
700
ATP
Ca -free2+
0
Depletion of ER store triggers store-operated Ca2+ entry that is necessary for ER store refilling
ER [Ca2+]
Cytoplasmic Ca2+
Solovyova & Verkhratsky, unpublished
27
[Ca2+
] i (nM
)
60
200
100 nM ET-3
Ca-free
200
50
50 s
[Ca2+
] i (nM
)
50 s
50 s
1 μM NA
Ca-free
ATP + NA
Ca-free
[Ca2+
] i (nM
)
60
200
Store-operated Ca2+ is universally present in all types of glia: Store-operated Ca2+ entry in Bergmann glial cells in situ
in cerebellar slice
Tuschick, Kirischuk, Kirchhoff, Liefeldt, Paul, Verkhratsky & Kettenmann, (1997): Cell Calcium, v. 21, p. 409-419.
28
[Ca2+
] i (nM
)
460
5 min
100 μM ATP
0 Ca
100
75 s
[Ca2+
] i (nM
)
60
400
250 s
A
B
0 Ca 0 Ca 0 Ca
100 μM ATP
100 μM ATP
Store-operated Ca2+ is universally present in all types of glia: Activation of purinoceptors triggers both Ca2+ release and store-operated Ca2+ entry in human glioma cells
Hartmann & Verkhratsky (1998): J Physiol, v. 513, p. 411-424.
29
80
450
[Ca2+
] i (nM
)
A
10 μM ATP 100 μM ATP 300 μM ATP
0 Ca 0 Ca 0 Ca
150 s
Δ[Ca2+]cap
[ATP] (μM)
120
80
40
0
1 10 100
Δ[C
a2+] ca
p (n
M)
B(98)
(81)
(12)(0)(0)
0
0.2
0.4
0.6
0.8
1.0
1.2
0.01 0.1 1 10 100[ATP] (μM)
Δ[C
a2+] i/Δ
[Ca2+
] i max
C
Ca2+ release
Ca2+ entry
KH 1.5
KH 7
Dissociation between activation of Ca2+ release and store-operated Ca2+ entry in human glioblastoma cells
Hartmann & Verkhratsky (1998): J Physiol, v. 513, p. 411-424.
30
G
InsP R3
Store-operated channel
Metabotropic receptor
InsP3
SERCA
ATP
ADPCa 2+
Ca release compartment
2+
Store-operated Ca2+ entry is controlled by specific portion of the ER possibly in the very vicinity of the plasmalemma
Hartmann & Verkhratsky (1998): J Physiol, v. 513, p. 411-424.
31
1500
microglia
600
100
1200
430
oligodendrocytes astrocytes
trp 6 5/4 3 2 1 6 5/4 3 2 1 6 5/4 3 2 1
Expression of TRP channels in glial cells
Kirchhoff & Verkhratsky, unpublished
32 Glial calcium signalling: mechanisms of generation
4. Glial cells generate calcium signals in response to neuronal activity
Release of neurotrasnmittters from presynaptic terminals activatesmetabotropic receptors in astroglial perysinaptic processes, that trigger Ca2+
signals. Similarly release of glutamate and ATP from electrically active axonsaxons trigger receptor/InsP3-mediated Ca2+ signals in oligodendroglia.
33
PCL
PF
Pia
BG
STIM
200 mμ
a b
c
12
10 mμ
1 22 s
d
2 s
1.6
1.0
F/F0
4 mμ
0
255
Parallel fibers stimulation triggers calcium signalsin Bergmann glial cell microdomains
Grosche, Matyash, Moller, Verkhratsky, Reichenbach & Kettenmann (1999): Nat Neurosci, v. 2 p. 139-143.
34
a
4 mμ
Control
TTX
Washout
2 s
1.0
1.5
F/F0
b
Control
Cd2+
2 s
1.0
1.35
F/F0
4 mμ
Inhibition of neuronal excitability abolishes Ca2+ signals in Bergmann glia
Grosche, Matyash, Moller, Verkhratsky, Reichenbach & Kettenmann (1999): Nat Neurosci, v. 2 p. 139-143.
35
Synaptically evoked Ca2+ signalling occurs in the microdomains represented by elementary structures which envelope groups of synapses
head
stalk
Grosche, Matyash, Moller, Verkhratsky, Reichenbach & Kettenmann (1999): Nat Neurosci, v. 2 p. 139-143.
36
50 s
1000 μM Glu 1000 μM Glu 1000 μM Glu
5 min 10 min
90
250
[Ca2+
] i (nM
)
A
90
230
1000 μM Glu1000 μM Glu 1000 μM Glu
5 min 10 min
[Ca2+
] i (nM
)
B 500 nM thapsigargin
500 nM thapsigargin
50 s
Ca2+-free
Glutamate induces Ca2+ release from thapsigargin-sensitive store
Kirischuk, Kirchhoff, Matyash, Kettenmann & Verkhratsky (1999): Neuroscience, v. 92, p. 1051-1059.
37
1000 μM glutamate
25 s
90
250
[Ca2+
] i (nM
)
A
1000 μM glutamate
25 s
90
250
[Ca2+
] i (nM
)
B
1000 μM glutamate
1000 μM glutamate
Control
Heparin
Heparine inhibits glutamate-induced Ca2+ signalling
Kirischuk, Kirchhoff, Matyash, Kettenmann & Verkhratsky (1999): Neuroscience, v. 92, p. 1051-1059.
38
mGluR1 mGluR5
N-term 7 TMD C-term N-term 7 TMD C-term
# 36 # b11
mGluR1
500
200M
mGluR5b
mGluR5a
b
a
b
a
c
15 ms
3 nA
A
C
B
Br Ø M 453647 42 b143 Br b11b10 b5
Vh = -70 mV
S1 AS2 AS1
S1 S2 AS1
Expression of mGluR 5 in Bergmann glia
Kirischuk, Kirchhoff, Matyash, Kettenmann & Verkhratsky (1999): Neuroscience, v. 92, p. 1051-1059.
39
Glial calcium signalling: mechanisms of generation
5. Stimulation of glial cells triggers propagating Ca2+ waves that spread throughglial syncytia
Mechanisms of propagating Ca2+ waves in astroglia are complex and involvediffusion of InsP3 through gap junctions and Ca2+ dependent release oftransmitters (most probably ATP).
40 Propagating calcium waves in astroglial confluent cultures were discoveredby Ann Cornell-Bell and her colleagues in 1990 and are seen in many preparations
in vitro and in situ
Astroglial calcium waves in retinaNewman & Zahs (1997) Science, v.275, p. 844-847
Calcium waves in cultured astrocytesCharles (1998) Glia, v.24, p. 39-49
41
Mechanisms of glial Ca2+ wave propagation
InsP3 diffusion through gap junctions; release of transmitters or combination of both
InsP3
InsP3
InsP3
InsP3
InsP3
InsP3
InsP3
InsP3
InsP3
InsP3Ca2+
Ca2+
Ca2+Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
ATP
ATP
ATP
ATP
ATP
Gap junction
Metabotropic (P2Y)receptor
ER Ca release2+
Vesicular release of neurotransmitter (ATP)
A
B
C
Verkhratsky & Butt (2007): Glial Neurobiology, A TextbookWiley & Sons
42
Sodium signalling in astroglia
43
Astroglial receptors and transporters regulate Ca2+ and Na+ fluxes 44 Stimulation of ionotropic glutamate receptors induces [Na+] elevation
Kirischuk, Kettenmann & Verkhratsky (2007): Pflugers Arch, 454, 245-252.
45
Application of glutamate triggers inward current and sodium influx
5
5
20
25
[Na
] (m
M)
+i
[Na
] (m
M)
+i
200 pA
200 pA
1000 M glutamateμ 1000 M glutamateμ
100 M CNQXμ Na -free (NMDG)+
100 M kainateμ
100 M kainateμ
100 M CNQXμ
30 s
30 s
Kirischuk, Kettenmann & Verkhratsky (2007): Pflugers Arch, 454, 245-252.
46 Stimulation of parallel fibers triggers inward current and [Na+]i elevation
Kirischuk, Kettenmann & Verkhratsky (2007): Pflugers Arch, 454, 245-252.
47
Sodium as a signalling molecule in astroglia?
Kirischuk, Parpura & Verkhratsky (2012) TINS, 35, 497-506
48
Conclusions
Stimulation of neuroglial cells with neurotransmitters and neuromodulatorstriggers cytosolic ionic (Ca2+and Na+) signals.
Glial Ca2+ signals are predominantly generated by Ca2+ release from theendoplasmic reticulum though opening of InsP3-gated Ca2+ channels (InsP3receptors).Endoplasmic reticulum membrane represents an excitable mediathat allows generation of propagating calcium waves, which integrateastroglial syncytia.Neuroglial Ca2+ signals can be instrumental for integrativeprocesses in neuronal-glial networks.
Glial Na+ signals are generated by Na+ entry through ionotropic receptors,TRP channels and transporetrs. Cytosolic Na+ concentration regulatemultiple homeostatic pathways.
49