Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Humer, C; Radiskovic, T; Horváti, K; Lindinger, S; Groschner, K; Romanin, C; Höglinger, C.
Bidirectional Allosteric Coupling between PIP2 Binding and the Pore of the Oncochannel TRPV6.
INT J MOL SCI. 2024; 25(1):
Doi: 10.3390/ijms25010618
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- Co-Autor*innen der Med Uni Graz
- Groschner Klaus
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- Abstract:
- The epithelial ion channel TRPV6 plays a pivotal role in calcium homeostasis. Channel function is intricately regulated at different stages, involving the lipid phosphatidylinositol-4,5-bisphosphate (PIP2). Given that dysregulation of TRPV6 is associated with various diseases, including different types of cancer, there is a compelling need for its pharmacological targeting. Structural studies provide insights on how TRPV6 is affected by different inhibitors, with some binding to sites else occupied by lipids. These include the small molecule cis-22a, which, however, also binds to and thereby blocks the pore. By combining calcium imaging, electrophysiology and optogenetics, we identified residues within the pore and the lipid binding site that are relevant for regulation by cis-22a and PIP2 in a bidirectional manner. Yet, mutation of the cytosolic pore exit reduced inhibition by cis-22a but preserved sensitivity to PIP2 depletion. Our data underscore allosteric communication between the lipid binding site and the pore and vice versa for most sites along the pore.
- Find related publications in this database (using NLM MeSH Indexing)
- Calcium - administration & dosage
- Cytosol - administration & dosage
- Binding Sites - administration & dosage
- Bone Density Conservation Agents - administration & dosage
- Phosphatidylinositols - administration & dosage
- Find related publications in this database (Keywords)
- TRPV6
- calcium
- PIP2
- cis-22a
- inhibition
- lipid