Calmodulin as a direct detector of Ca2+ signals.
Many forms of signal transduction occur when Ca(2+) enters the cytoplasm of a cell. It has been generally thought that there is a fast buffer that rapidly reduces the free Ca(2+) level and that it is this buffered level of Ca(2+) that triggers downstream biochemical processes, notably the activation of calmodulin (CaM) and the resulting activation of CaM-dependent enzymes. Given the importance of these transduction processes, it is crucial to understand exactly how Ca(2+) activates CaM. We have determined the rate at which Ca(2+) binds to CaM and found that Ca(2+) binds more rapidly to CaM than to other Ca(2+)-binding proteins. This property of CaM and its high concentration support a new view of signal transduction: CaM directly intercepts incoming Ca(2+) and sets the free Ca(2+) level (that is, it strongly contributes to fast Ca(2+) buffering) rather than responding to the lower Ca(2+) level set by other buffers. This property is crucial for making CaM an efficient transducer. Our results also suggest that other Ca(2+) binding proteins have a previously undescribed role in regulating the lifetime of Ca(2+) bound to CaM and thereby setting the gain of signal transduction.
Department of Neurology, University of California Los Angeles, Los Angeles, California, USA. gfaas@ucla.edu
Guido C
GC
Faas
Sridhar
S
Raghavachari
John E
JE
Lisman
Istvan
I
Mody
D000818:Animals; D064026:Calbindins; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002147:Calmodulin / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D064030:S100 Calcium Binding Protein G / Q000378:metabolism
D064026:Calbindins; D002147:Calmodulin; D064030:S100 Calcium Binding Protein G; D002118:Calcium
Nature. 2009 Mar 19;458(7236):299-304
19295602
Nat Rev Neurosci. 2005 Apr;6(4):267-76
15803158
Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8842-7
9238065
Neuron. 1999 Mar;22(3):549-58
10197534
Neuron. 2002 Jan 31;33(3):439-52
11832230
J Biol Chem. 2003 Dec 12;278(50):49667-70
14551202
J Neurosci. 2005 Jan 19;25(3):558-65
15659591
Biophys J. 2000 Dec;79(6):3009-18
11106608
Biophys J. 1996 Feb;70(2):1069-81
8789126
Anal Biochem. 1994 Aug 1;220(2):227-37
7978263
J Neurosci. 2002 Mar 1;22(5):1648-67
11880495
Exp Brain Res. 1984;56(2):323-6
6479265
PLoS Biol. 2007 Nov;5(11):e311
18044987
J Physiol. 1992 May;450:273-301
1331424
J Neurosci. 2000 Mar 1;20(5):1831-6
10684884
J Neurosci. 1997 Jul 15;17(14):5357-65
9204920
Clin Endocrinol (Oxf). 1985 Aug;23(2):201-18
2996810
PLoS One. 2007 Oct 24;2(10):e1073
17957255
Annu Rev Physiol. 2008;70:23-49
17988210
J Neurosci. 2006 Aug 2;26(31):8183-94
16885232
Science. 2005 Nov 4;310(5749):866-9
16272125
Biophys J. 2005 Jun;88(6):4421-33
15778435
Proc Natl Acad Sci U S A. 1988 Sep;85(17):6571-5
3137570
J Biol Chem. 2004 Sep 17;279(38):39374-82
15262982
Biophys J. 2007 Dec 1;93(11):3848-59
17704141
J Biol Chem. 2002 May 10;277(19):16662-72
11872749
J Neurophysiol. 2008 Jan;99(1):264-76
17959737
J Physiol. 2000 Jun 1;525 Pt 2:405-18
10835043
J Biol Chem. 1991 May 5;266(13):8050-4
1902469