DOI: 10.1161/CIRCULATIONAHA.114.010675
Nuclear Calcium Transients: Hermes Propylaios in the Heart
Running title: da Costa Martins et al.; Nuclear calcium transients
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Paula A. da Costa Martins, PhD; Stefanos Leptidis, PhD; Leon J. De Windt, PhD
Department of Cardiology, School for Cardiovascular Diseases, Faculty of Health, M
edi
dicine and
Medicine
Life
f Sciences, Maastricht Univer
rsiity
t , Maastricht, The Ne
Neth
t erlands
Life
University,
Netherlands
Address
A
ddress forr Correspondence:
Corr
rresp
rr
ponden
en
ncee:
Leon
Le
on J.
J. De Windt,
Win
ndt,
dt, PhD
PhD
Department
D
epartment ooff Ca
Card
Cardiology
rdio
iolo
logy
gy
School
S
h l for
f Cardiovascular
C di
l Diseases,
Di
Faculty
F l off Health,
H l h Medicine
M di i andd Life
Lif Sciences
S i
Maastricht University
Maastricht, The Netherlands
Tel: +31-43-388-2949
Fax: +31-43-387-1055
E-mail: [email protected]
Journal Subject Code: Basic science research:[130] Animal models of human disease
Key words: calcium transient, Editorial, signaling - electrophysiology
1
DOI: 10.1161/CIRCULATIONAHA.114.010675
“…O cunning guide, son of Maia, I fear that you might steal my lyre and my curved bow. For
you hold the office from Zeus to establish deeds of exchange among men throughout the fertile
earth. But if you would suffer to swear the great oath of the gods for me, either by nodding your
head or by the mighty water of the Styx, you would accomplish everything pleasing to my own
heart...” (Homeric Hymnes)
In Greek Mythology, Hermes (Greek: ‫ۉ‬ȡȝ‫ݨ‬Ȣ), son of Zeus and the pleiad Maia, was perhaps the
most complex deity of transitions and boundaries, contemporarily simplified as messenger god
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
that moved freely between the higher worlds at Olympus, our world with human mortals and the
grim underworld of the deceased. As second youngest of the Olympian gods andd symbolizing
sym
y bo
ym
boli
lizi
li
zing
ing
sandals,
Hermes' function as divine messenger, he is often
f sculptured as a youngster with winged sandals
winged
cap,
holding
staff,
kerykeion,
wing
wi
nged
ng
ed cap
ap
p, aand
ndd ho
hold
l ing his symbolic herald's st
taff,
f, the Greek ke
ery
r keeio
on, consisting of two
snakes
winged
Hermes
received
multiple
including
Propylaios,
nak
kes wrapped
ed aaround
roun
un
nd a wi
wing
ng
ged sstaff.
taff
ta
fff. H
erm
mes re
eceiveed m
ece
ultip
iplle eepithets
pith
ith
hetts in
nclud
cludin
ingg Pr
in
rop
pyl
ylaaioos,
freely
gateway",
significance
free
fr
eeely ttranslated
rans
ra
nsla
ns
late
la
tedd ass ""at
at tthe
he ga
he
ate
t wa
way"
y",, reflecting
y"
reefl
flec
ecti
ec
ting
ti
ng a deeper
dee
eepe
peer philosophical
phiilos
ph
osop
op
phi
hica
c l si
ca
ign
g iffic
ican
ance
an
ce ooff Hermes.
Herm
He
rm
mes.
es.
with
all
imaginary
Greek
deities,
Hermes’
actions
As w
itth al
ll im
imag
aginar
ag
aryy Gr
ar
Gree
e k de
ee
eit
itie
iees,, H
erme
er
mess’ ac
me
cti
tion
onss do nnot
on
ot ddescribe
escr
es
crib
cr
ibee a uniformly
ib
unif
un
iffor
orml
m y positive
positivve
character. Tales rather tell a complex, three-layered personality, ranging from a truly uplifting
spirit as would be expected from his divine roots, to a character with an innocent yet cunning
nature, but at times he also displayed unexpected evil. With these three faces, Hermes likely
symbolized how our Greek ancestors segmented the universe, consisting of a noble and divine
upper world physically located at Mount Olympus; planet Earth with all its living creatures
including mankind; and finally, the dark side of disease, suffering and death, represented by the
underworld.
Cytoplasmic calcium and excitation contraction coupling
2
DOI: 10.1161/CIRCULATIONAHA.114.010675
The multi-faceted roles that calcium plays in the heart may well bare analogy to the mythological
character Hermes. First and foremost, for the maintenance of cardiac contraction, there may be
no more important ion than calcium. During each heartbeat, a small leak of calcium through
voltage-dependent L-type calcium channels (VDLC) triggers massive calcium release from the
sarcoplasmatic reticulum (SR) through SR bound ryanodine receptors (RyR2) into the cytoplasm
of heart muscle cells, which triggers muscle contraction in a process referred to as excitationcontraction coupling.1 Cardiac relaxation is initiated by the concerted action of the
sodium/calcium exchanger and muscle-specific SR calcium ATPase-2 (SERCA2), which reDownloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
sequesters calcium into the internal calcium storage pool, allowing for the next quantal release of
calcium. On top of this elaborate system of dedicated calcium release channels aand
nd ccalcium
nd
alci
alci
c um
pumps, the ȕ-adrenergic receptor system controls the magnitude of the calcium transient by
ac
ctiiva
vati
ting
ti
ngg pprotein
ro
otein
in
n kkinase
i ase A, a kinase that by virtu
in
tuee ooff its direct ph
tu
hos
o ph
hor
oryylation of the calcium
activating
virtue
phosphorylation
eleeas
a e channe
els an
nd calcium
nd
callci
cium
um ppumps
um
mps aallows
lloows fo
or in
ntrraceell
ellula
larr calc
ccalcium
alcciu
um tr
ran
nsiient
ents
ts w
i h hi
it
high
ghher
er
release
channels
and
for
intracellular
transients
with
higher
am
mpl
plit
itud
it
u e an
ud
andd fa
astter ddecay.
eccay
ay.
amplitude
faster
Hear
rt failure
fail
fa
i ur
il
uree iss characterized
chaara
r ct
c erriz
ized
ed
d byy disturbed
dist
di
sttur
urbe
b d excitation-contraction
be
exci
ex
c taati
t on
on-c
-ccon
ontr
t ac
acti
tiion coupling,
cou
oupl
pllin
ing,
g ssystolic
g,
ystolic and
ys
Heart
diastolic abnormal contractile properties, fueling speculations that correcting the calcium
transient may form a rationale to recover cardiac contractility. Indeed, the cornerstone of
contemporary heart failure pharmacotherapy is ȕ-adrenergic blockade2, 3 and at least one
rationale for its therapeutic benefit is suppression of the hyperadrenergic state and restore normal
RyR2 calcium release channel function in patients with heart failure.4 On top of that, at least one
new therapeutic strategy aimed to normalize calcium transients in heart failure has now reached
clinical stages where viral-mediated gene therapy is directed to increase SERCA2a expression to
improve SR Ca2+ reuptake.5
3
DOI: 10.1161/CIRCULATIONAHA.114.010675
Nucleoplasmic calcium transients
Secondly, each cytoplasmic calcium transient also elicits nucleoplasmic calcium transients,
which is a far less studied rhythmic phenomenon that also takes place simultaneously during
cardiac contraction.6 Potentially, alterations in the kinetics or amplitude of nucleoplasmic
calcium transients may have functional ramifications, because this pool of calcium represents the
prime candidate to influence calcium-dependent gene regulatory signaling events in a
phenomenon referred to as excitation-transcription coupling.7 Indeed, a vast body of literature
indicates that calcium/calmodulin acts as an important second messenger in the heart
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
downstream of growth factors, adrenergic signaling and mechanical stretch that have the ability
o trigger hypertrophic growth of the myocardium.8 Immediate recipient signals for
forr calcium
cal
alci
al
cium
ci
um as
as
to
second
econd messenger are the calcium/calmodulin-dependent phosphatase calcineurin,9 which
en
nab
able
less translocation
le
tran
tr
ansl
an
sloccat
sl
atiion
io of the transcription factor NFAT
NFA
AT to the nucl
cleu
e s an
andd in turn activates
enables
nucleus
transcriptional
ran
nsc
s riptionaal pathways
path
hwaayss that
tha
hatt reprogram
reprog
repr
ogra
og
ram
m cardiac
card
rd
diaac gene
genne expression
expre
xpreesssio
ionn eeither
ith
ther
err aalone
lonne
lo
ne oorr by aactivating
ctiv
ct
ivat
atin
ing
ng
10
additional
ad
ddi
d ti
tion
o al hhypertrophic
on
yper
yp
erttrooph
ophic tr
tra
transcription
ansc
scri
sc
riipt
ptio
ionn fa
io
fact
factors
ctor
ct
orss in
or
including
ncl
c udi
uding
ing GA
GATA
GATA4,
TA4,
TA
4 M
4,
MEF2
EF22 oorr H
EF
Hand2.
and2
an
d .99,, 10
d2
Alternatively,
y, calcium/calmodulin-dependent
cal
a ci
cium
um/c
um
/ccalmo
modu
mo
duli
du
linli
n de
nd pe
pend
nden
nd
entt protein
en
prot
pr
o ei
ot
e n kinase
kiina
nase
se (CaMK)
(Ca
CaMK
MK)) si
MK
sign
gnaali
gn
l ng rrelieves
e ie
el
ieve
v s histoneve
signaling
deacetylase (HDAC)-dependent repression of MEF2 transcriptional activity and facilitates the
induction of MEF2-responsive gene expression.11
Nucleoplasmic calcium transients obey distinct boundaries, involve different partners,
and play by slightly different rules than their cytoplasmic counterparts. First, the main store for
nucleoplasmic calcium transients is formed by the nuclear envelope. As such, the nuclear
envelope not only contributes to nuclear structure and insulation from the surrounding
cytoplasm, but also serves as the main reservoir for bidirectional transport of calcium ions and
allows bidirectional transport of macromolecular complexes. The balance between release and
4
DOI: 10.1161/CIRCULATIONAHA.114.010675
storage of calcium in the nuclear envelope is regulated by calcium release channels, including
the RyR2 and inositol 1,4,5-trisphosphate receptor (IP3R), Ca2+-buffering proteins, and calcium
pumps (SERCA2) that refill the nuclear envelope with calcium,12 reminiscent to the
sarcoplasmatic reticulum storage control.
Prior characterizations of the nucleoplasmic calcium transient established that generation
of the systolic calcium peak likely involves both a passive and an active component. The passive
component is probably mediated by cytoplasmic calcium diffusion through nuclear pore
complexes to increase nuclear calcium concentration, since the amplitude of the nuclear calcium
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
transient is proportional to the amplitude of the cytoplasmic calcium transient.13 However,
several
everal lines of evidence also indicate that the nucleus is capable of actively stori
storing
riing and
nd rreleasing
elea
el
e sing
ea
calcium ions, since individually studied myocytes displayed prominently higher nucleoplasmic
diastolic
di
iassto
toli
licc ca
li
calc
calcium
lciium
lc
m concentration
co
and higher nucleoplasmic
nucleo
eopplasmic systolicc calcium
eo
callci
ciuum
um peaks.13 This
observation
obbserv
seer ation iss iin
n li
line
inee w
with
itth th
thee fact
factt tthat
h t eendothelin-1
ha
ndoothelinn-11 ca
can
an in
indu
induce
d ce aan
du
n in
inde
independent
deppendden
de
nt in
increase
ncr
c ea
e se iin
n
nuclear
form
calcium
nucl
nu
c ea
cl
earr calcium
calc
ca
lciu
lc
ium
iu
m without
wiith
thooutt changing
chan
ch
ngi
ging
ng cytosolic
cyto
cy
to
osooli
licc calcium
caalc
l iu
um transients,
trran
nsi
sieents
ents
ts,, and
and th
tthat
at tthis
hiss fo
hi
orm
m ooff ca
alcciu
ium
m
release
elease orig
originates
gin
nat
a es
e ffrom
rom
ro
m pe
pperinuclear
rinu
ri
nucllea
nu
earr st
sstores.
orres
es.14
Stimulation of heart rate frequency increases systolic nuclear calcium in parallel with
cytoplasmic systolic calcium, but diastolic nuclear calcium rises substantially higher than their
cytoplasmic counterparts, demonstrating a slower decay of the nucleoplasmic calcium transient
and a much higher buildup of nuclear calcium when diastole is shortened.13 Whether this
frequency-dependent physiological maneuver has implications for excitation-transcription
coupling has remained unclear to date. In conclusion, prior studies support the idea that calcium
release from the nuclear envelope at least in part plays an active role in nuclear calcium transient
generation and fed speculations that nucleoplasmic transients may possibly alter in and
5
DOI: 10.1161/CIRCULATIONAHA.114.010675
contribute to pathophysiological processes.
Nucleoplasmic calcium transients and excitation-transcription coupling
In this issue of Circulation, a novel report from the group of Pieske and coworkers now adds
valuable new information to the pathophysiology of nuclear calcium homeostasis15. Ljubojevic et
al. used a cross-species and multidisciplinary approach to systematically compare the structural
and functional changes of the nuclear envelope and nuclear calcium handling in myocytes
derived from the healthy myocardium, the early hypertrophic phase and late stage heart failure.15
In short, early during hypertrophy, the authors observed an increased nuclear size and less
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
frequent intrusions (invaginations) of the nuclear envelope into the nuclear lumen.
alc
l iu
ium
m re
rele
leas
le
ae
Accompanying these ultrastructural changes, a reduced expression of thee ca
calcium
release
channel RyR2 and the calcium pump SERCA2, versus an increase in IP3R, and a differential
ocaali
liza
zati
za
tion
ti
on ooff th
hes
esee various calcium transporter
rs att the nuclear envelope
en
nve
v lo
ope were observed. Most
localization
these
transporters
mportantly,
po
nnuclear
ucle
uc
lear
ar calcium
cal
alci
cium
ci
um transients
trans
ranssieent
ntss displayed
disppla
layyed ddiminished
imiiniish
shed
ed amplitudes,
ampli
mplitu
tude
d s, lengthening
leng
engthe
gtheeni
ning
n of
ng
of nuclear
nucl
nu
c ear
importantly,
ran
nsiien
entt duration
duura
rati
tion
onn and
and increased
inncre
ncreas
assed
d diastolic
dia
iast
stoolic
ol c calcium
calci
al ium le
eveels,
s, reminiscent
rem
emin
inis
in
issceent
n tto
o cyto
ccytoplasmic
yto
opl
plas
a mi
as
micc ca
alcciu
ium
m
transient
levels,
calcium
ransients fro
om fa
ffailing
ilin
il
ingg my
in
m
ocyt
oc
y ess.1 Finally,
Fin
i al
ally
ly,, the
ly
the ultrastructural
u tr
ul
t as
astr
t ucctu
tr
tura
rall ch
ra
chan
changes
a ge
an
gess of tthe
he eenvelope
nvel
nv
elop
el
opee and
op
transients
from
myocytes.
alterations in nucleoplasmic transients were accompanied by a higher activation status of
CAMKII and concomitant nuclear export of HDAC4, suggesting a functional contribution of the
altered nucleoplasmic transient in excitation-transcription coupling. These data therefore provide
a plausible explanation for the mode of activation of calcium/calmodulin-induced gene
regulatory systems in the earliest phases of heart failure.
As with all breakthrough studies, these new observations also provoke a myriad of new
questions that will stimulate the exploration of new experimental horizons. One less obvious
question would start with asking the rationale for the mere existence of nuclear transients in the
6
DOI: 10.1161/CIRCULATIONAHA.114.010675
healthy heart. Likely, our lack of understanding this phenomenon must be related to a fine-tuned
comprehension of the genomic architecture that may require calcium-dependent processes for
normal nuclear function. As similar findings have been observed in other organs besides the
heart,16 it is expected that our field will witness the birth of new disciplines and technologies,
including nuclear electrophysiology and optimized fluorescent reporter systems.17 Other
questions are whether the tubular invaginations of the nuclear envelope resemble sarcolemmal Ttubuli, allowing juxtaposition of as of yet to be discovered critical calcium release channels and
fine-tuned control of nuclear calcium, and what mechanism provokes the observed reduction of
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
nuclear pore intrusions. On a more molecular level, readily testable hypotheses that now arise are
post-transsla
lati
tiionnal
al
whether the various calcium release channels and pumps also undergo post-translational
modifications similar to their counterparts at the sarcolemma and SR, and if so, at which amino
accid
d ssites,
ites
it
es, co
ccontrolled
ntrooll
lled
e by which balance of kinases
ed
es/p
es
/phhosphatases an
nd wh
hat functional
acid
kinases/phosphatases
and
what
amifications
mi
th
hesee biochemical
biooche
bi
oche
hemi
mica
mi
call changes
ca
ch
hang
angess may
maay provoke.
proovokee. A particularly
parrti
ticu
cu
ulaarl
rlyy in
iintriguing
trig
ig
gui
uing
ng aaspect
sppec
ectt of tthe
he
ramifications
these
cu
urr
rren
en
nt study
stud
st
ud
dy is the
thee observation
obseerva
erv tiion
o that
that with
wit
i h higher
high
hi
gher
gh
er hheart
eaart
r rrate
atee fre
at
ffrequency,
requ
q ency
ency
cy,, nuc
nnuclear
uclea
cleaar di
ddiastolic
assto
olicc ca
alc
lciu
iu
um
current
calcium
n in
incr
crrea
ease
seed to
o a much
muc
uchh higher
high
hi
ghher extent
ext
x en
entt by a sslower
lo
owe
werr decay
deca
de
cayy than
ca
than cytoplasmic
cyt
ytop
o la
op
lasm
smic
sm
ic transients.
transients.15
concentration
increased
It is tempting to speculate that the frequency dependent rise in diastolic nuclear calcium is
causally related to the activation of pro-hypertrophic gene regulatory cascades and translates to
the often elevated heart rates of heart failure patients. Indeed, the SHIFT trial data demonstrate a
beneficial effect of lowering heart rate by ivabradine in patients with advanced systolic heart
failure, both in terms of attenuated LV remodeling and less frequent hospitalizations.18 To more
firmly establish whether tachycardia is causally related to the earlier phases of cardiac
remodeling, animal models of heart failure can be placed on heart rate lowering medication and
simultaneously monitor nuclear calcium transients, cardiac remodeling and disease symptoms.
7
DOI: 10.1161/CIRCULATIONAHA.114.010675
Notwithstanding these as of yet unanswered questions, the current study is in support of
the premise that the nuclear ultrastructure is causally related with alterations in nuclear calcium
transient generation and the pathophysiological phenomenon of excitation-transcription
coupling. The multi-faceted functions of the seemingly simple ion calcium transversing physical
boundaries and communicating at the level of the sarcomere, nuclear integrity and excitationtranscription coupling are not unlike mythological Hermes, influencing the divine sarcomeric
contraction, homeostatic nuclear calcium transients in life and igniting myocardial disease and
death.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Award
Funding Sources: P.D.C.M. was supported by a Leducq Career Development Aw
war
ardd an
andd th
thee
from
Dutch Heart Foundation grant NHS2010B261. L.D.W. acknowledges support fr
rom
m tthe
he
Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation
off University
Uni
nivvers
versit
sit
ityy Medical
Meedic
dical Centers, the Netherlands Organization
Orgganization for Health
Healt
ltth Research
Research and
Development
(ZonMW)
Royal
Netherlands
Academy
Sciences.
L.D.W.
further
D
evvelopmen
ve
nt (Z
ZonnMW
MW)) an
andd th
thee Ro
Roya
yall Ne
ya
Neth
ther
th
errla
lannds Ac
cad
adem
emyy of S
em
cien
ci
ence
en
cees. L
.D.W
.D
.W.. wa
.W
wass fu
furt
rthe
rt
herr
he
supported
Fondation
Leducq
Transatlantic
Network
Excellence
08-CVD-03
upp
ported by
y tthe
hee F
onddattion
nL
educ
u q Tr
ran
nsatllan
ntic N
etwo
et
work
wo
rk off Ex
xcellen
ncee pprogram
rogr
ro
g am
gr
m 088-CV
CVD--033
CV
andd gr
grant
European
Research
Council
(ERC).
an
gran
antt 311549
an
3115
31
1549
49 from
fro
rom
m th
thee Eu
uro
rope
pean
pe
an R
esea
es
earc
ea
rchh Co
rc
Coun
unci
un
ciil (E
(ERC
RC).
RC
).
Conflict of Interest Disclosures: None.
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Class
11
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Nuclear Calcium Transients: Hermes Propylaios in the Heart
Paula A. da Costa Martins, Stefanos Leptidis and Leon J. De Windt
Circulation. published online June 13, 2014;
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