Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels.

The Rho family of small guanosine triphosphatases (Rho GTPases: RhoA, Cdc42, and Rac1) regulates many aspects of cell behavior, including actin dynamics and cell migration. The generation of calcium ion (Ca(2+)) microdomains is critical in promoting cell migration because they control the localized activity of Rho GTPases. We identified receptor-activated TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6) channels as antagonistic regulators of actin remodeling and cell motility in fibroblasts and kidney podocytes.

Identification of a protein-protein interaction between KCNE1 and the activation gate machinery of KCNQ1.

KCNQ1 channels assemble with KCNE1 transmembrane (TM) peptides to form voltage-gated K(+) channel complexes with slow activation gate opening. The cytoplasmic C-terminal domain that abuts the KCNE1 TM segment has been implicated in regulating KCNQ1 gating, yet its interaction with KCNQ1 has not been described. Here, we identified a protein-protein interaction between the KCNE1 C-terminal domain and the KCNQ1 S6 activation gate and S4-S5 linker.

Secondary structure of a KCNE cytoplasmic domain.

Type I transmembrane KCNE peptides contain a conserved C-terminal cytoplasmic domain that abuts the transmembrane segment. In KCNE1, this region is required for modulation of KCNQ1 K(+) channels to afford the slowly activating cardiac I(Ks) current. We utilized alanine/leucine scanning to determine whether this region possesses any secondary structure and to identify the KCNE1 residues that face the KCNQ1 channel complex.

KCNE3 truncation mutants reveal a bipartite modulation of KCNQ1 K+ channels.

The five KCNE genes encode a family of type I transmembrane peptides that assemble with KCNQ1 and other voltage-gated K(+) channels, resulting in potassium conducting complexes with varied channel-gating properties. It has been recently proposed that a triplet of amino acids within the transmembrane domain of KCNE1 and KCNE3 confers modulation specificity to the peptide, since swapping of these three residues essentially converts the recipient KCNE into the donor (Melman, Y.F.