A Caveolae-Targeted L-Type Ca2+ Channel Antagonist Inhibits Hypertrophic Signaling Without Reducing Cardiac Contractility

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