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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.07-9694comv1 fj.07-9694comv2 22/5/1540    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mederos y Schnitzler, M. Articles by Chubanov, V. PubMed PubMed Citation Articles by Mederos y Schnitzler, M. Articles by Chubanov, V.

Evolutionary determinants of divergent calcium selectivity of TRPM channels

Institute for Pharmacology and Toxicology, Philipps-University Marburg, Marburg, Germany

²Correspondence: Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Karl-von-Frisch-Str.1, 35043 Marburg, Germany. E-mail: chubanov{at}staff.uni-marburg.de

The mammalian TRPM gene family can be subdivided into distinct categories of cation channels that are either highly permeable for Ca²⁺ (TRPM3/6/7), nonselective (TRPM2/8), or even Ca²⁺ impermeable (TRPM4/5). TRPM6/7 are fused to -kinase domains, whereas TRPM2 is linked to an ADP-ribose phosphohydrolase (Nudix domain). At a molecular level, the evolutionary steps that gave rise to the structural and functional TRPM channel diversity remain elusive. Here, we provide phylogenetic evidence that Nudix-linked channels represent an ancestral type of TRPMs that is present in various phyla, ranging from protists to humans. Surprisingly, the pore-forming segments of invertebrate TRPM2-like proteins display high sequence similarity to those of Ca²⁺-selective TRPMs, while human TRPM2 is characterized by a loss of several conserved residues. Using the patch-clamp technique, Ca²⁺ imaging, and site-directed mutagenesis, we demonstrate that restoration of only two "ancient" pore residues in human TRPM2 (Q981E/P983Y) significantly increased (4-fold) its permeability for Ca²⁺. Conversely, introduction of a "modern" sequence motif into mouse TRPM7 (E1047Q/Y1049P) resulted in the loss of Ca²⁺ permeation and a linear TRPM2-like current-voltage relationship. Overall, our findings provide an integrative view on the evolution of the domain architecture and the structural basis of the distinct ion permeation profiles of TRPM channels.—Mederos y Schnitzler, M., Wäring, J., Gudermann, T., Chubanov, V. Evolutionary determinants of divergent calcium selectivity of TRPM channels.

Key Words: transient receptor potential • TRPM2 • TRPM7 • TRPM8 • Nudix