162
Calcium Biochemistry
and purifed to a single protein band
corresponding to 260 kDa. However, the
molecular weight oF the native receptor
is about 1 million Da, indicating that the
receptor is a homotetramer.
IP
3
receptors can be phosphorylated
by diFFerent kinases (PKA, PKC, CaM
kinase II) in a stoichiometric manner,
resulting in a reduced potency oF IP
3
in releasing Ca
2
+
From the ER. Thus,
regulation oF the IP
3
-induced Ca
2
+
release
by phosphorylation oF the receptor is
a means oF ‘‘communication’’ between
diFFerent second messenger systems.
Cloning and sequencing oF cDNA oF
the IP
3
receptor was frst accomplished
by Mikoshiba et al. IP
3
receptors From
diFFerent species revealed a high degree oF
conservation and homology. The sequence
Further demonstrates a high degree oF
similarity to the ryanodine-binding Ca
2
+
-
release channel oF the SR with which it
also shares Functional similarity. Like the
latter, the main protein mass protrudes
into the cytosol with both the N- and
the C-terminus being on the cytosolic
side, resulting in an even number oF
transmembrane domains. The IP
3
binding
site
lies
within
the
frst
400
amino
acids From the N-terminus, whereas the
putative Ca
2
+
channel is located within the
transmembrane regions oF the C-terminal
end, indicating a large spatial distance
For coupling the IP
3
binding to the Ca
2
+
release through a conFormational change.
6.2.2
The Ca
2
+
-release Channel
The sarcoplasmic reticulum (SR) oF stri-
a
t
e
dm
u
s
c
l
e
si
sa
nim
p
o
r
t
a
n
tF
e
a
t
u
r
e
involved
in
the
regulation
oF
excita-
tion–contraction coupling oF muscles. It
is composed basically oF two elements:
(1) the
longitudinal
tubules
surround-
ing the myofbrils and (2) the terminal
cisternae. The latter are in contact with
the transverse tubular system (T-tubules),
a periodic inflection From the plasma
membrane (the sarcolemma) Forming a
junctional gap that is crossed by periodic
‘‘Feetlike’’ structures. These structures,
originally described as the ryanodine re-
ceptor (RyR), have been identifed as the
calcium-release channel oF the SR, Form-
ing tetramers as Functional units. The
amino acid sequence oF the monomer,
consisting oF more than 5000 amino acids,
has been deduced From the cDNA by the
group oF Numa. An unusual Feature oF
these proteins is the existence oF only
Four potential transmembrane domains
right at the C-terminal end indicating that
more than 90% oF the protein protrudes
into the cytosol. This, on the other hand,
would provide an attractive morphologi-
cal explanation For the existence oF these
‘‘Feetlike’’ structures spanning the 150-
˚
A
gap between the SR and the T-tubules and,
Furthermore, would provide the possibil-
ity For a physical interaction between the
Ca
2
+
-release channel oF the SR and the
voltage-dependent Ca
2
+
channel concen-
trated in the T-tubules and identifed as
dihydropyridine receptors or L-type Ca
2
+
channels (see above). These Features would
provide a rational explanation For a direct
triggering oF Ca
2
+
release by these Ca
2
+
channels located in the T-tubules.
Three distinct RyRs have been iden-
tifed. RyR1 is predominantly expressed
in skeletal muscles, RyR2 in heart and
brain, and RyR3 in some regions oF the
brain (e.g. hippocampus, diencephalon).
Even iF RyR was originally described as
the Ca
2
+
-release channel oF the sarcoplas-
mic reticulum, it is now well known that
RyR is also widely distributed in nonmus-
cle cells. In these cells, cyclic ADP-ribose
appears to be the natural second messen-
ger For inducing Ca
2
+
release From the
channel.
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