Identification of secreted protein 1 (SEP1) as a new interaction partner of ASIC1

Acid-sensing ion channel 1 (ASIC1) is a trimeric ion channel, opened by a fast drop of extracellular pH. ASIC1 is highly abundant in the CNS and present at the postsynapse. In slice recordings of the lateral amygdala, it was shown, that ASIC1 can be activated by protons co-released by transmitter exocytosis, thus contributing to synaptic transmission. Intriguingly, ASIC1-dependent current was small compared to currents of GABA or Glutamate receptors, however, ASIC1 was reported to have a significant impact on various physiological and pathophysiological processes e.g. fear related behavior, long-term potentiation and stroke. In contrast, other reports showed that either little acidification or even alkalinization of the synaptic cleft during synaptic transmission, questioning the role of ASIC1a. Thus, the physiological function of ASIC1 in the CNS is still not fully understood. We reasoned that identifying accessory and regulatory proteins of ASIC1 may enhance our understanding of the channel and its physiological role. In a recent knock-out controlled proteomic screen from mouse brain we identified secreted protein 1 (SEP1) as possible interaction partner of ASIC1. In HEK cells, SEP1 strongly increases current density (3-5 fold, p<0.001) without changing the biophysical properties of ASIC1a. Interestingly, in neurons of SEP1-/- mice ASIC currents are completely absent, suggesting a crucial role for ASIC1 functionality. SEP1 is secreted and when applied from extracellular enhances ASIC1a current amplitudes in cells not expressing SEP1 indicating a possible transcellular effect of SEP1. In addition, we were able to show, that SEP1 is endocytosed and transported back to the ER.