Your browser doesn't support javascript.
loading
Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1/4/5 channels.
Rubaiy, Hussein N; Ludlow, Melanie J; Henrot, Matthias; Gaunt, Hannah J; Miteva, Katarina; Cheung, Sin Ying; Tanahashi, Yasuyuki; Hamzah, Nurasyikin; Musialowski, Katie E; Blythe, Nicola M; Appleby, Hollie L; Bailey, Marc A; McKeown, Lynn; Taylor, Roger; Foster, Richard; Waldmann, Herbert; Nussbaumer, Peter; Christmann, Mathias; Bon, Robin S; Muraki, Katsuhiko; Beech, David J.
Afiliação
  • Rubaiy HN; Schools of Medicine.
  • Ludlow MJ; Schools of Medicine.
  • Henrot M; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany.
  • Gaunt HJ; Schools of Medicine.
  • Miteva K; Schools of Medicine.
  • Cheung SY; Schools of Medicine.
  • Tanahashi Y; Schools of Medicine; Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan.
  • Hamzah N; Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom.
  • Musialowski KE; Schools of Medicine.
  • Blythe NM; Schools of Medicine.
  • Appleby HL; Schools of Medicine.
  • Bailey MA; Schools of Medicine.
  • McKeown L; Schools of Medicine.
  • Taylor R; Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom.
  • Foster R; Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom.
  • Waldmann H; Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
  • Nussbaumer P; Lead Discovery Center GmbH, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany.
  • Christmann M; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany.
  • Bon RS; Schools of Medicine.
  • Muraki K; School of Pharmacy, Aichi-Gakuin University, 1-100 Kusumoto, Chikusa, Nagoya 464-8650, Japan. Electronic address: kmuraki@dpc.aichi-gakuin.ac.jp.
  • Beech DJ; Schools of Medicine. Electronic address: d.j.beech@leeds.ac.uk.
J Biol Chem ; 292(20): 8158-8173, 2017 05 19.
Article em En | MEDLINE | ID: mdl-28325835
The concentration of free cytosolic Ca2+ and the voltage across the plasma membrane are major determinants of cell function. Ca2+-permeable non-selective cationic channels are known to regulate these parameters, but understanding of these channels remains inadequate. Here we focus on transient receptor potential canonical 4 and 5 proteins (TRPC4 and TRPC5), which assemble as homomers or heteromerize with TRPC1 to form Ca2+-permeable non-selective cationic channels in many mammalian cell types. Multiple roles have been suggested, including in epilepsy, innate fear, pain, and cardiac remodeling, but limitations in tools to probe these channels have restricted progress. A key question is whether we can overcome these limitations and develop tools that are high-quality, reliable, easy to use, and readily accessible for all investigators. Here, through chemical synthesis and studies of native and overexpressed channels by Ca2+ and patch-clamp assays, we describe compound 31, a remarkable small-molecule inhibitor of TRPC1/4/5 channels. Its potency ranged from 9 to 1300 pm, depending on the TRPC1/4/5 subtype and activation mechanism. Other channel types investigated were unaffected, including TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8, and store-operated Ca2+ entry mediated by Orai1. These findings suggest identification of an important experimental tool compound, which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. The compound should greatly facilitate future studies of these ion channels. We suggest naming this TRPC1/4/5-inhibitory compound Pico145.
Assuntos
Palavras-chave

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Bloqueadores dos Canais de Cálcio / Canais de Cátion TRPC Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Bloqueadores dos Canais de Cálcio / Canais de Cátion TRPC Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2017 Tipo de documento: Article