Homer proteins are a family of scaffolding proteins which may play an important role in calcium signaling by facilitating the assembly of signaling complexes in neuronal cells. Among the three splice variants of Homer 1, Homer 1alpha is rapidly up-regulated by neural stimulation and may regulate the disassembly of signaling complexes mediated by Homer proteins. In spite of its potential importance in calcium signaling, the regulation of Homer 1alpha expression in cardiac myocytes has never been investigated. In this study, we examined the regulation of Homer 1alpha expression in cardiac myocytes. Homer 1alpha was significantly up-regulated by several hypertrophic agonists, including endothelin-1 (ET-1), phenylephrine, isoprotenerol and angiotensin-II, and ET-1 most strikingly induced Homer 1alpha expression. The induction of Homer 1alpha expression by ET-1 peaked at 2 h and inhibitors for mitogen-activated/extracellular signal regulated kinase (MEK) significantly suppressed the induction of Homer 1alpha. This study first clarified the regulation of Homer 1alpha expression in cardiac myocytes and demonstrated that ET-1 induced Homer 1alpha expression through the mitogen-activated protein kinase pathway.