Your browser doesn't support javascript.
loading
From molecular phylogeny towards differentiating pharmacology for NMDA receptor subtypes.
Platt, Randall J; Curtice, Kigen J; Twede, Vernon D; Watkins, Maren; Gruszczynski, Pawel; Bulaj, Grzegorz; Horvath, Martin P; Olivera, Baldomero M.
Afiliación
  • Platt RJ; Department of Biology, University of Utah, Salt Lake City, UT 84112, USA.
  • Curtice KJ; Department of Biology, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: kigen.curtice@utah.edu.
  • Twede VD; Department of Biology, University of Utah, Salt Lake City, UT 84112, USA.
  • Watkins M; Department of Biology, University of Utah, Salt Lake City, UT 84112, USA.
  • Gruszczynski P; Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA; Intercollegiate Faculty of Biotechnology and Chemistry, University of Gdansk, 80-952 Gdansk, Poland; Medical University of Gdansk, 80-822 Gdansk, Poland.
  • Bulaj G; Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
  • Horvath MP; Department of Biology, University of Utah, Salt Lake City, UT 84112, USA.
  • Olivera BM; Department of Biology, University of Utah, Salt Lake City, UT 84112, USA.
Toxicon ; 81: 67-79, 2014 Apr.
Article en En | MEDLINE | ID: mdl-24508768
In order to decode the roles that N-methyl-D-aspartate (NMDA) receptors play in excitatory neurotransmission, synaptic plasticity, and neuropathologies, there is need for ligands that differ in their subtype selectivity. The conantokin family of Conus peptides is the only group of peptidic natural products known to target NMDA receptors. Using a search that was guided by phylogeny, we identified new conantokins from the marine snail Conus bocki that complement the current repertoire of NMDA receptor pharmacology. Channel currents measured in Xenopus oocytes demonstrate conantokins conBk-A, conBk-B, and conBk-C have highest potencies for NR2D containing receptors, in contrast to previously characterized conantokins that preferentially block NR2B containing NMDA receptors. Conantokins are rich in γ-carboxyglutamate, typically 17-34 residues, and adopt helical structure in a calcium-dependent manner. As judged by CD spectroscopy, conBk-C adopts significant helical structure in a calcium ion-dependent manner, while calcium, on its own, appears insufficient to stabilize helical conformations of conBk-A or conBk-B. Molecular dynamics simulations help explain the differences in calcium-stabilized structures. Two-dimensional NMR spectroscopy shows that the 9-residue conBk-B is relatively unstructured but forms a helix in the presence of TFE and calcium ions that is similar to other conantokin structures. These newly discovered conantokins hold promise that further exploration of small peptidic antagonists will lead to a set of pharmacological tools that can be used to characterize the role of NMDA receptors in nervous system function and disease.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Filogenia / Receptores de N-Metil-D-Aspartato / Conotoxinas Límite: Animals Idioma: En Revista: Toxicon Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Filogenia / Receptores de N-Metil-D-Aspartato / Conotoxinas Límite: Animals Idioma: En Revista: Toxicon Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido