Activation of (Na ⁺ + K ⁺)-ATPase modulates cardiac L-type Ca ²⁺ channel function

Cellular Ca ²⁺ 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 Ca ²⁺ movement remain enigmatic. We have found recently that activation of the (Na ⁺ + K ⁺)-ATPase markedly potentiates intracellular Ca ²⁺ transients and contractility of rat heart cells. Little is known about the pathway responsible for the activation of the (Na ⁺+ K ⁺ )-ATPase-initi- ated Ca ²⁺ signaling. Here, we demonstrate a novel mechanism in which activation of the (Na ⁺ + K ⁺)-ATPase is coupled to increased L-type Ca ²⁺ channel function through a signaling cascade involving Src and ERK1/2 but not well established regulators of the channel, such as adrenergic recepto system or activation of PKA or CaMKII. We have also identified Ser ¹⁹²⁸, a phosphorylation site for the α1 subunit of the L-type Ca ²⁺ channel that may participate in the activation of the (Na ⁺ + K ⁺)-ATPase-mediated Ca ²⁺ signaling. The findings reported here uncover a novel molecular cross-talk between activation of the (Na ⁺+ K ⁺ )-ATPase and L-type Ca ²⁺ channel and provide new insights into Ca ²⁺ signaling mechanisms for deeper understanding of the nature of cellular Ca ²⁺ handling in heart.