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J. Biol. Chem., Vol. 276, Issue 25, 22359-22367, June 22, 2001
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From the Laboratoire de Neurobiologie Cellulaire, CNRS FRE 2180, 5 rue Blaise Pascal, 67084 Strasbourg, France
When opened by depolarization,
L-type calcium channels are rapidly inactivated by
the elevation of Ca2+ concentration on the cytoplasmic
side. Recent studies have shown that the interaction of calmodulin with
the proximal part of the cytoplasmic C-terminal tail of the channel
plays a prominent role in this modulation. Two motifs interacting with
calmodulin in a Ca2+-dependent manner have been
described: the IQ sequence and more recently the neighboring CB
sequence. Here, using synthetic peptides and fusion proteins derived
from the Cav1.2 channel combined with biochemical
techniques, we show that these two peptides are the only motifs of the
cytoplasmic tail susceptible to interact with calmodulin. We determined
the Kd of the CB interaction with calmodulin to be
12 nM, i.e. below the Kd of
IQ-calmodulin, thereby precluding a competitive displacement of CB by
IQ in the presence of Ca2+. In place, we demonstrated that
a ternary complex is formed at high Ca2+ concentration,
provided that calmodulin and the peptides are initially allowed to
interact at a low Ca2+ concentration. These results provide
evidence that CB and IQ motifs interacting together with calmodulin
constitute a minimal molecular switch leading to
Ca2+-induced inactivation. In addition, we suggest that
they could also be the tethering site of calmodulin.
Interactions of Calmodulin with Two Peptides Derived from the
C-terminal Cytoplasmic Domain of the Cav1.2
Ca2+ Channel Provide Evidence for a Molecular Switch
Involved in Ca2+-induced Inactivation*
*
This work was supported by the CNRS and by a doctoral
fellowship from the Ministère de l'Education Nationale de la
Recherche et de la Technologie attributed to J. Mouton.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 33-388-45-66-34;
Fax: 33-388-60-16-64; E-mail:
maulet@neurochem.u-strasbg.fr.
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