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Membrane Transport Processes Analyzed by a Highly Parallel Nanopore Chip System at Single Protein Resolution
Published on: August 16, 2016
Targeting Two-Pore Channels: Current Progress and Future Challenges
Xuhui Jin1, Yuxuan Zhang1, Abeer Alharbi1
1Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
Abstract:
Two-pore channels (TPCs) are cation-permeable channels located on endolysosomal membranes and important mediators of intracellular Ca2+ 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.
Insights
Two-pore channels (TPCs) are crucial for calcium signaling and implicated in diseases like cancer. Understanding TPC activation and developing direct modulators are key for future therapeutic strategies.
Area of Science:
- Cellular Biology
- Molecular Physiology
- Pharmacology
Background:
- Two-pore channels (TPCs) are endolysosomal cation channels vital for intracellular calcium (Ca2+) signaling.
- TPCs influence critical cellular processes including growth, metabolism, and cancer progression.
- Current research limitations include reliance on indirect inhibitors (Ned-19) and TPC knockout models, hindering mechanistic understanding.
Purpose of the Study:
- To review recent advancements in understanding TPC structure, function, and activation mechanisms.
- To discuss the development of direct pharmacological modulators for TPCs.
- To highlight the therapeutic potential of targeting TPCs.
Main Methods:
- Review of recent structural biology studies on TPCs.
- Analysis of interactome data to identify TPC-interacting proteins.
- Compilation of data on existing and emerging pharmacological modulators of TPCs.
Main Results:
- Recent structural insights are facilitating the development of direct TPC modulators.
- Understanding TPC activation mechanisms remains a significant challenge.
- Targeting TPCs therapeutically is an emerging but promising area.
Conclusions:
- Advances in TPC structural biology and interactome studies are paving the way for novel drug development.
- Direct pharmacological modulation of TPCs holds significant therapeutic potential.
- Further research is essential to fully elucidate TPC function and enable targeted therapies.
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