158
Calcium Biochemistry
Structurally, all VOC-type channels are
complexes of four or Fve subunits (
α
1,
α
2,
β
,
γ
,and
δ
) forming large macromolecular
complexes. The best-characterized exam-
ples are the
L
-type channels. The represen-
tative from skeletal muscle is composed of
two high molecular weight components,
α
1and
α
2, plus three smaller subunits
β
,
γ
,and
δ
. The channel protein represents
a multigene family. To date, 10 distinct
genes for the
α
1-subunit and three differ-
ent ones for the
β
-subunit have been iden-
tiFed in mammals. The
α
1-subunit reveals
some properties characteristic of voltage-
g
a
t
edch
ann
e
l
s
.I
ti
sc
omp
o
s
edo
ff
ou
r
homologous repeated units containing six
transmembrane regions and contains the
conduction pore, the voltage sensor, and
sites for gating and for channel regula-
tion, for example, by protein kinases, by
toxins, and by drugs. Dihydropyridines
(e.g. nifedipine), phenylalkylamines (e.g.
verapamil), and benzothiazepines (e.g. dil-
tiazem) bind to three allosterically cou-
pled binding sites on the
α
1-subunit. A
physiologically important means of reg-
ulating these channels is provided by
cAMP-dependent (PKA) phosphorylation
increasing the opening probability of the
channels. In reconstituted systems, it was
shown that the
α
1- and
β
-subunits could be
phosphorylated by PKA in a stoichiometric
manner.
Three
different
kinds
of
r
eceptor-
o
perated
Ca
2
+
c
hannels
(ROC)
have
been identiFed. They are activated by
L-glutamate
and are named after the
different agonists binding to these recep-
tors as kainate (KA),
α
-amino-3-hydroxy-
5-methyl-4-isoxazole proprionate (AMPA),
or as N-methyl-D-aspartate (NMDA) recep-
tors. They are located in the postsynaptic
membrane. Most channels formed by KA
and AMPA receptors are primarily per-
meable to Na
+
or K
+
,bu
tsomeo
fthe
AMPA receptors are also permeable to
Ca
2
+
, whereas the NMDA receptors are
permeable to Na
+
and Ca
2
+
. Several genes
have been identiFed characterizing the dif-
ferent types of glutamate receptors. The
mass of the different receptors ranges from
95 to 165 kDa.
In neuroendocrine cells, activation of
an inward Ca
2
+
current occurs through
channels known as store-operated Ca
2
+
channels (SOC). These channels have not
been characterized in detail on the pro-
tein level, but they are homologous to
the transient receptor potential (
trp
or
trp
-like) gene products of
Drosophila
.The
mechanism by which these intracellular
stores, probably derived from the en-
doplasmic reticulum, communicate their
Ca
2
+
level to the plasma membrane in
the form of a channel-opening signal is
still under debate. The process, termed
capacitative calcium entry
(CCE) mediates
smaller Ca
2
+
influx than the voltage-gated
channels. Two hypotheses for the mech-
anism of CCE are discussed: one favors
the liberation of a small chemical factor
inducing the opening of the CCE chan-
nel, the other proposes some form of
physical interaction between the ER and
the plasma membrane CCE to trigger the
opening.
6.1.2
The Ca
2
+
Pump
The Ca
2
+
pump of plasma membranes
(PMCA) is important for the Fne-tuning
of the intracellular free Ca
2
+
concentra-
tion. It belongs to the P-type ion-motive
ATPases like its counterpart from the
endo (sarco)plasmic reticulum, the SERCA
pump; that is, it forms an aspartylphos-
phate
intermediate
to
transport
Ca
2
+
against its concentration gradient across
the plasma membrane on the expense
of ATP. It is a protein of low abun-
dance (e.g. 0.1% of the total membrane
