Calcium Biochemistry
similar to other CaM-dependent kinases
with catalytic, autoinhibitory, and CaM
binding domains. In addition, CaMKK
contains an unusual arginine–proline rich
insert within the N-terminal part of its
catalytic domain that might be important
for the recognition of CaMKI and IV as
substrates since deletion of these inserts
abolishes its activation potential toward
CaMKI and IV.
CaMKK can be found both in the cy-
toplasm and in the nucleus; the latter is
important for the activation of CaMKIV
that is mainly responsible for the Ca
dependent gene expression. In this con-
text, it is interesting to note that the
distribution of
CaMKK in the brain is
much more similar to CaMKIV, and that
CaMKK follows the distribution of
CaMKI, suggesting that
CaMKK could be
the actual activator of CaMKIV, whereas
CaMKK would be that of CaMKI. Nev-
ertheless, both isoforms of CaMKK can
activate CaMKI and IV with the same
efFciency, but whether there exist more
speciFc isoforms and whether there are
additional kinases further upstream like
in the MAP-kinase cascade is not known
to date.
Neuronal Calcium Sensors
A group of E±-hand proteins that has re-
cently received attention is that of the
neuronal calcium sensors (NCS). They
are divided into Fve subfamilies. Two of
them are expressed in retinal photore-
ceptors, called recoverins and guanylate
cyclase-activating proteins (GCAPs), the
three others frequenins, visinin-like pro-
teins, and the Kv channel–interacting
proteins. Recoverins and GCAPs have
antagonistic roles in phototransduction:
recoverin inhibits rhodopsin kinase and
GCAPs activate guanylate cyclase. The
other three NCS families are supposed to
regulate the release of neurotransmitters,
the biosynthesis of polyphosphoinositides,
the metabolism of cyclic nucleotides, or
the activity of Kv channels. Most NCSs are
N-terminally myristoylated, favoring inter-
action with membranes (or target proteins)
in a Ca
-dependent manner. Thus, the
-dependent myristoyl switch could be
a means to compartmentalize signaling
cascades in neurons or to transduce Ca
signals to the membranes.
S100 Proteins
The multigenic family of the so-called S100
proteins (named because they are soluble
at 100% ammonium sulfate solution) is
growing steadily, and possible functions
have been implicated in intracellular and
extracellular regulatory activities. To this
family belong proteins that are involved
in cell cycle control (e.g. calcyclin) or
can display neurite growth factor activities
such as the S100
dimer. S100B was the
Frst member of the E±-hand family that
is secreted to perform its extracellular
function as a growth factor. The latter
function is exclusively connected with the
-isoform and only so if it can form a
dimer. Mutation of one of the cysteine
residues necessary for the dimer formation
leads to the loss of this function. Recently,
it has been suggested that the S100
dimer carries out its growth factor function
through the RAGE receptor (receptor for
advanced glycation end products).
In general, members of the S100 protein
family have low molecular weights (
between 9 and 14 kDa). They usually
function as homodimers, but some also
as heterodimers. Of special note is the
Fnding reported by Heizmann et al. that
in human S100A1–S100A13 are clustered
on chromosome 1 (1q21) within 5 Mb, but
a common regulation of expression has
not been observed.
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