Abstract

Cellular Ca²⁺ signaling underlies diverse vital biological processes, including muscle contractility, memory encoding, fertilization, cell survival, and cell death. Despite extensive studies, the fundamental control mechanisms that regulate intracellular Ca²⁺ movement remain enigmatic. We have found recently that activation of the (Na⁺+K⁺)-ATPase markedly potentiates intracellular Ca²⁺ transients and contractility of rat heart cells. Little is known about the pathway responsible for the activation of the (Na⁺+K⁺)-ATPase-initiated Ca²⁺ signaling. Here, we demonstrate a novel mechanism in which activation of the (Na⁺+K⁺)-ATPase is coupled to increased L-type Ca²⁺ channel function through a signaling cascade involving Src and ERK1/2 but not well established regulators of the channel, such as adrenergic receptor system or activation of PKA or CaMKII. We have also identified Ser¹⁹²⁸, a phosphorylation site for the α1 subunit of the L-type Ca²⁺ channel that may participate in the activation of the (Na⁺+K⁺)-ATPase-mediated Ca²⁺ signaling. The findings reported here uncover a novel molecular cross-talk between activation of the (Na⁺+K⁺)-ATPase and L-type Ca²⁺ channel and provide new insights into Ca²⁺ signaling mechanisms for deeper understanding of the nature of cellular Ca²⁺ handling in heart.