The source of Ca2+ to activate pathological cardiac hypertrophy is not clearly defined. Ca2+ influx through the L-type Ca2+ channels (LTCCs) determines “contractile” Ca2+, which is not thought to be the source of “hypertrophic” Ca2+. 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 Ca2+ to activate the calcineurin–nuclear factor of activated T-cell signaling cascade that promotes pathological hypertrophy.Methods and Results:
We developed reagents that targeted Ca2+ 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 Ca2+ influx-induced NFAT nuclear translocation, but it did not reduce myocyte contractility.Conclusions:
We provide proof of concept that Ca2+ influx through LTCCs within caveolae signaling domains can activate “hypertrophic” signaling, and this Ca2+ influx can be selectively blocked without reducing cardiac contractility.