Key concepts of excitation-conttraction cou
upling
Sign
nals in stria
ated muscle
e. The conttraction of striated
s
mus cle is contro
olled by rap
pid changess of cytosolic
c
Ca2++.concentration, [Ca2+]c. But Ca2+ re
egulates multiple cell fun
nctions, span
nning from m
milliseconds to years. To
o
stay separate, Ca
C 2+ signals
s are coded in spatial and
a
tempora
al patterns, the fastest of which invvolve 100 to
o
2+
1000
0-fold [Ca ]c changes in
n ~1 ms. The
T system must
m
be cap
pable of
emingly
explo
osively fast jumps but must
m
never explode.
e
Th
hese two see
contradictory prroperties arre realized by a sarco
oplasmic re
eticulum
mbrane with
h channels organized in structural-functiona
al units
mem
named couplons
s 1.
A co
ouplon (figs
s 1 and 2) is
i the array of RyRs an
nd their asssociated
prote
eins on one side of a tria
ad junction. In non mam
mmals it add
ditionally
inclu
udes RyR off isoform 3 or β in the para-junctio
on. Synch
hronized
open
ning is starte
ed by an allo
osteric signal2 from the voltage
v
(Vm) sensor3
in th
he membran
ne of the tra
ansverse tub
bule, leading
g to depolarrizationinduced Ca2+ rellease, DICR.
FFig. 1. The couuplon—array of RyRs and
thheir associateed proteins: trriadin, junctin
aand calsequesstrin.
Allos
stery94, a notion
n
first introduced in EC coupling by Ríoss et al.,
1993
345, is any mechanical
m
in
nfluence cau
using a chan
nge in a “diffferent place”” from that o
of contact. T
The DHPR to
o
RyR
R signal is one example
e of “verticall” allosterics
s in the cou plon (fig 4 illustrates “vvertical” and
d “horizontal”
direcctions of pos
ssible alloste
eric actions).)
CICR
R. Clusterring of RyR
Rs in couplo
ons allows further coo
ordination, e
either by
horizzontal (RyR
R-to-RyR) allosterics, orr Ca2+-induc
ced Ca2+ re
elease, CICR, which
manifests itself as Ca2+ sp
parks (Chen
ng et al., 19
993). The existence of CICR,
gs with it
wherreby Ca2+ re
elease chan
nnels are ac
ctivated to open by Ca2++ itself, bring
the paradox off control4, i.e. why ac
ctivation do
oes not pro
opagate explosively.
Coup
plons are fin
nite (no more
e than ~60 channels
c
in the mouse) and separa
ate, which
expla
ains the pa
aradox. Th
he whole system
s
does
s not explo
ode simply because
1
excittation usuallly stays re
estricted to individual couplons
c
. CICR, and
d sparks,
42,17
requ
uire the RyR3 , locate
ed in the parra-junction. The RyR1 sstrictly align
n with the
Vm-ssensing system (fig 3), which
w
preven
nts their eng
gaging in CIC
CR51. Local disarray
5
allow
ws productio
on of sparks .
Fig 2. Couploon (from 89),
circles represent DHPRs.
Term
mination. The fast term
mination of Ca2+release
e is equally important ffor a fast
transsient. It is
s due to de
e-activation of DHPRs upon repo
olarization, complemented by Ca22+-dependen
nt
6-8
inacttivation (CD
DI ) and possibly allosterics. Bo
oth activatio
on and term
mination of signals are
e subject to
o
modulation from
m inside the SR, through
h powerful processes—i
p
including “ve
ertical” allossterics—that we are only
y
startting to underrstand8.
gue. These events rep
peat at frequ
uencies of 10-100
1
Hz, for brief periods of
Fatig
activvity that in turn repeat at
a different frequencies, depending
g on muscle
e, motor
unit and fiber type.
t
Repeated activity leads to
o fatigue, w
which coursses with
9
subsstantial altera
ation of Ca movements
m
.
ease. The go
oal of our laboratory has
s been to de
efine these ““Ca2+ movem
ments in
Dise
2+
EC ccoupling”. In
n fact, the piicture of Ca signaling presented a
above was iin some
measure built with advances
s produced by our laborratory and la
argely complleted by
meth
hods originated here. We
W now use these metho
ods to learn
n whether, ho
ow, and
why Ca2+ move
ements are altered in disease. We
W will app
ply them to
o select
cond
ditions with altered co
ouplons, wh
hich model muscle disseases or muscle
repe
ercussions off systemic diseases.
D
DHPR
C
RyR
R
V
Jn
T
Tr
Casq
FFig 3. Horizonntal and
vvertical allosteerics in the
ccouplon.