Targeting Two-Pore Channels: Current Progress and Future Challenges

Abstract

Two-pore channels (TPCs) are cation-permeable channels located on endolysosomal membranes and important mediators of intracellular Ca ²⁺ signalling. TPCs are involved in various pathophysiological processes, including cell growth and development, metabolism, and cancer progression. Most studies of TPCs have used TPC ^–/– cell or whole-animal models, or Ned-19, an indirect inhibitor. The TPC activation mechanism remains controversial, which has made it difficult to develop selective modulators. Recent studies of TPC structure and their interactomes are aiding the development of direct pharmacological modulators. This process is still in its infancy, but will facilitate future research and TPC targeting for therapeutical purposes. Here, we review the progress of current research into TPCs, including recent insights into their structures, functional roles, mechanisms of activation, and pharmacological modulators.

Highlights

• Two-pore channel (TPC)-mediated endolysosomal Ca ²⁺ signalling regulates a variety of processes, including cell proliferation, differentiation, metabolism, viral infection, and cardiac function.

• Despite the well-established model that TPCs are Ca ²⁺-selective channels indirectly activated by nicotinic acid adenine dinucleotide phosphate (NAADP), it has also been proposed that TPCs as Na ⁺ channels are activated directly by phosphatidylinositol 3,5-bisphosphate [PI(3,5)P ₂].

• 3D structures of mouse TPC1 and human TPC2 were recently determined, which made it possible for structure-based virtual screening methods to identify pharmacological modulators of TPC.

• Recent identification by high-throughput screens of pharmacological modulators that target TPCs will help reveal the molecular mechanisms underlying the role of endolysosomal Ca ²⁺ signalling in different pathophysiological processes, and to develop new therapeutics.