Presenilin (PS) is a transmembrane protein identified in familial early-onset Alzheimer disease, and it is mainly expressed in cell membranes and organelle membranes. As an important catalytic core of the γ-secretase multimeric enzyme complex, PS has been implicated in regulating various proteins. Recent researches have shown that mutations in PS are identified in the familial dilated cardiomyopathy, and the PS gene plays an important role in cardiac formation and regulation of calcium homeostasis in myocardial cells. In this review, we summarized the function of PS in heart and the mechanisms underlying the effects of PS on calcium homeostasis, such as amyloid β protein (Aβ), 1,4,5-inositol trisphosphate receptors, ryanodine receptors and PS as endoplasmic reticulum (ER) Ca²⁺ leak channels, hoping to provide a theoretical basis for the therapy of dilated cardiomyopathy.