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Voltage-driven Ca2+-Binding at the L-type Ca2+-Channel Triggers Cardiac EC-Coupling Prior to Ca2+-Influx.
MedLine Citation:
PMID:  23145875     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The activation of the ryanodine Ca2+-release channels (RyR2) by Ca2+ entry through the L-type Ca2+-channels (Cav1.2) is believed to be the primary mechanism of Excitation-Contraction (EC) coupling in cardiac cells. This proposed mechanism of Ca2+-induced-Ca2+-release (CICR), cannot fully account for the lack of a termination signal for this positive feedback process. Using Cav1.2 channel mutants, we demonstrate that the Ca2+-impermeable α11.2/L775P/T1066Y mutant introduced through lentiviral-infection into neonate cardiomyocytes, triggers Ca2+-transients independently of Ca2+-influx. In contrast, the α11.2/L775P/T1066Y/4A mutant, in which the Ca2+-binding site of the channel was destroyed, supports neither the spontaneous nor the electrically evoked-contractions. Ca2+ bound at the channel selectivity filter appears to initiate a signal that is conveyed directly from the channel pore to RyR2, triggering contraction of cardiomyocytes prior to Ca2+ influx. Thus, RyR2 is activated in response to a conformational change in the L-type channel during membrane-depolarization and not through interaction with Ca2+ ions diffusing in the junctional gap space. Accordingly, termination of the RyR2 activity is achieved when the signal stops upon returning of the L-channel to the resting-state. We propose a new model in which the physical link between Cav1.2 and RyR2 enables propagation of a conformational change induced at the open pore of the channel to directly activate RyR2. These results highlight Cav1.2 as a signaling protein and provide a mechanism for terminating Ca2+ release from the RyR2 through protein-protein interactions. In this model, the L-type channel is a master regulator of both initiation and termination of EC-coupling in neonate cardiomyocytes.
Authors:
Liron Suzanne Gez; Yamit Hagalili; Asher Shainberg; Daphne Atlas
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-13
Journal Detail:
Title:  Biochemistry     Volume:  -     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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