LAUSR

Significance The potent vasopressor angiotensin II is released acutely during blood pressure control, and chronically during heart failure as a physiological strategy to increase cardiac output. We propose a mechanism, whereby angiotensin II signaling in ventricular myocytes stimulates hydrolysis of a membrane phospholipid called PIP2, triggering CaV1.2 channel internalization, and providing a means to acutely tune cellular excitability and modulate cardiac excitation-contraction coupling. Accordingly, this study presents data that supports a novel mechanistic role of PIP2 as a stabilizer of CaV1.2 channel expression on the sarcolemma of ventricular myocytes. Moreover, we provide the evidence that physiological signaling pathways alter cardiac PIP2 levels, and thus this work has implications for the many cardiac ion channels and exchangers regulated by PIP2.