A caveolae-targeted L-type Ca²+ channel antagonist inhibits hypertrophic signaling without reducing cardiac contractility.
BACKGROUND
The source of Ca(2+) to activate pathological cardiac hypertrophy is not clearly defined. Ca(2+) influx through the L-type Ca(2+) channels (LTCCs) determines "contractile" Ca(2+), which is not thought to be the source of "hypertrophic" Ca(2+). However, some LTCCs are housed in caveolin-3 (Cav-3)-enriched signaling microdomains and are not directly involved in contraction. The function of these LTCCs is unknown.


OBJECTIVE
To test the idea that LTCCs in Cav-3-containing signaling domains are a source of Ca(2+) to activate the calcineurin-nuclear factor of activated T-cell signaling cascade that promotes pathological hypertrophy.


RESULTS
We developed reagents that targeted Ca(2+) channel-blocking Rem proteins to Cav-3-containing membranes, which house a small fraction of cardiac LTCCs. Blocking LTCCs within this Cav-3 membrane domain eliminated a small fraction of the LTCC current and almost all of the Ca(2+) influx-induced NFAT nuclear translocation, but it did not reduce myocyte contractility.


CONCLUSIONS
We provide proof of concept that Ca(2+) influx through LTCCs within caveolae signaling domains can activate "hypertrophic" signaling, and this Ca(2+) influx can be selectively blocked without reducing cardiac contractility.
Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Catherine A
CA
Makarewich
Robert N
RN
Correll
Hui
H
Gao
Hongyu
H
Zhang
Baohua
B
Yang
Remus M
RM
Berretta
Victor
V
Rizzo
Jeffery D
JD
Molkentin
Steven R
SR
Houser
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000473:pathology / Q000503:physiopathology*; D002415:Cats; D021941:Caveolae / Q000187:drug effects* / Q000378:metabolism; D051244:Caveolin 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D051244:Caveolin 3; D050778:NFATC Transcription Factors; D018343:Receptors, Adrenergic, beta-2; D002118:Calcium