A scaffold attachment factor PHM-2 regulates synaptic transmission through SLO-2 potassium channel in C. elegans

Abstract Scaffold attachment factor B (SAFB) proteins are evolutionarily conserved DNA/RNA binding proteins that are involved in multiple processes of gene expression. These proteins are broadly expressed with particular high expression observed in the nervous system. However, their physiological roles in neurons are largely unclear. Here we show that PHM-2, the sole SAFB ortholog in C. elegans , regulates synaptic transmission at the neuromuscular junctions through an effect on SLO-2 potassium channel. We found that phm-2 knockout suppresses a sluggish phenotype of worms expressing a hyperactive SLO-2 channel, greatly reduces SLO-2-mediated neuronal whole-cell currents, and enhances neuromuscular synaptic transmission. In addition, we found that PHM-2 genetically interacts with another DNA/RNA binding protein, HRPU-2/hnRNP U, to control SLO-2 expression through a posttranscriptional mechanism. These results reveal a novel function of a SAFB protein in regulating neuronal activity, and may help understand the physiological roles of SAFB proteins in the nervous system of other species. Author Summary Proteins in the SAFB family are found in many species, and they help control how genes are expressed in cells. These proteins are commonly present in the nervous system, but their exact roles in nerve cells are not well understood. In this study, we examined the single SAFB-like protein called PHM-2 in the nematode C. elegans to learn how it affects the nervous system. We discovered that PHM-2 plays an important role in communication between nerve cells and muscles. Worms lacking PHM-2 were able to counteract the sluggish movement caused by a hyperactive potassium channel called SLO-2. Without PHM-2, nerve cells had much smaller electrical currents mediated by SLO-2 and a stronger signaling from nerves to muscles. We also found that PHM-2 works together with another genetic regulator, HRPU-2, to control the amount of SLO-2 protein made in nerve cells. These findings reveal a new role for SAFB proteins in shaping neuronal activity by regulating potassium channels. Understanding this process in worms may provide clues about how these proteins contribute to brain function in humans.