Cyclic nucleotide dependent regulation of fibroblast migration by multi drug resistant protein 4

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Role of cyclic nucleotides and cyclic nucleotide‐dependent signaling molecules in cell migration has long been known. However, the concept that it is not just the absence or presence, but a highly coordinated balance between cyclic nucleotides that regulates cell migration, is new and revolutionary. In this study, we used multi‐drug resistance protein 4 (MRP4)‐expressing cell lines and MRP4 knockout mice as model systems and wound healing assays as the experimental system to explore this unique and emerging concept. MRP4, an ATP binding cassette transporter protein, localizes to the plasma membrane and functions as a nucleotide efflux transporter and plays a role in the regulation of intracellular cyclic nucleotide levels. Here we demonstrate that mouse embryonic fibroblasts (MEFs) isolated from Mrp4−/− mice have higher intracellular cyclic nucleotide levels and migrate faster compared to MEFs from Mrp4+/+ mice. In contrast to these moderate increases seen in the absence of MRP4, a robust increase in cAMP levels was observed following treatment with forskolin and IBMX, which inhibits fibroblasts migration. In response to externally added cell‐permeant cyclic nucleotides (cpt‐cAMP and cpt‐cGMP), MEF migration appears to be biphasic. Altogether our data provide the first experimental evidence supporting the novel concept that balance between cyclic nucleotides is critical for fine‐tuned cell migration.