Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany
Fong Tsuen Tseung
Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany
Leonor Correia
Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany
Eva Schmidt
Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany
Anna Rössig
Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany
Susanna Zierler
Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany; Institute of Pharmacology, Johannes Kepler University Linz, Linz, Austria
Institute of Physiology II, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Catrin Swantje Müller
Institute of Physiology II, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Wolfgang Bildl
Institute of Physiology II, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Uwe Schulte
Institute of Physiology II, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, Freiburg, Germany
Institute of Physiology II, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, Freiburg, Germany
The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed membrane protein consisting of ion channel and protein kinase domains. TRPM7 plays a fundamental role in the cellular uptake of divalent cations such as Zn2+, Mg2+, and Ca2+, and thus shapes cellular excitability, plasticity, and metabolic activity. The molecular appearance and operation of TRPM7 channels in native tissues have remained unresolved. Here, we investigated the subunit composition of endogenous TRPM7 channels in rodent brain by multi-epitope affinity purification and high-resolution quantitative mass spectrometry (MS) analysis. We found that native TRPM7 channels are high-molecular-weight multi-protein complexes that contain the putative metal transporter proteins CNNM1-4 and a small G-protein ADP-ribosylation factor-like protein 15 (ARL15). Heterologous reconstitution experiments confirmed the formation of TRPM7/CNNM/ARL15 ternary complexes and indicated that complex formation effectively and specifically impacts TRPM7 activity. These results open up new avenues towards a mechanistic understanding of the cellular regulation and function of TRPM7 channels.
