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Calmodulin supports both inactivation and facilitation of L-type calcium channels
L-type Ca2+ channels support Ca2+ entry into cells, which triggers cardiac contraction, controls hormone secretion from endocrine cells and initiates transcriptional events that support learning and memory. These channels are examples of molecular signal-transduction units that regulate themselves t...
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Published in: | Nature (London) 1999-05, Vol.399 (6732), p.159-162 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | L-type Ca2+ channels support Ca2+ entry into
cells, which triggers cardiac contraction, controls hormone
secretion from endocrine cells and initiates transcriptional
events that support learning and memory. These channels are
examples of molecular signal-transduction units that regulate themselves through
their own activity. Among the many types of voltage-gated Ca2+
channel, L-type Ca2+ channels particularly display inactivation
and facilitation, both of which are closely linked to the earlier entry of
Ca2+ ions. Both forms of
autoregulation have a significant impact on the amount of Ca2+
that enters the cell during repetitive activity, with major consequences downstream.
Despite extensivebiophysical analysis, the molecular basis
of autoregulation remains unclear, although a putative Ca2+-binding
EF-hand motif, and a nearby consensus calmodulin-binding
isoleucine-glutamine ('IQ') motif,
in the carboxy terminus of the α1C channel subunit have been
implicated,. Here we show that calmodulin
is a critical Ca2+ sensor for both inactivation and facilitation,
and that the nature of the modulatory effect depends on residues within the
IQ motif important for calmodulin binding. Replacement of the native isoleucine
by alanine removed Ca2+-dependent inactivation and unmasked
a strong facilitation; conversion of the same residue to glutamate eliminated
both forms of autoregulation. These results indicate that the same calmodulin
molecule may act as a Ca2+ sensor for both positive and negative
modulation. |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/20200 |