Journal
BIOCHEMICAL JOURNAL
Volume 445, Issue -, Pages 29-38Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20120471
Keywords
calcium entry; Homer; Orai1; platelet; stromal interaction molecule 1 (STIM1); thrombin; transient receptor potential canonical (TRPC)
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Funding
- MINECO (Spanish Ministry of Economy and Competitiveness) [BFU2010-21043-C02-01]
- Junta de Extremadura-FEDER (Fondo Europeo de Desarrollo Regional) [GR10010]
- MEC (Ministerio de Educacion y Ciencia) [BFU2007-60104, BES-2011-043356]
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Horner is a family of cytoplasmic adaptor proteins that play different roles in cell function, including the regulation of G-protein-coupled receptors. These proteins contain an Ena (Enabled)/VASP (vasodilator-stimulated phosphoprotein) homology 1 domain that binds to the PPXXF sequence motif, which is present in different Ca2+-handling proteins such as IP3 (inositol 1,4,5-trisphosphate) receptors and TRPC (transient receptor potential canonical) channels. In the present study we show evidence for a role of Homer proteins in the STIM1 (stromal interaction molecule 1)-Orai1 association, as well as in the TRPC1-IP3RII (type II IP3 receptor) interaction, which might be of relevance in platelet function. Treatment of human platelets with thapsigargin or thrombin results in a Ca2+-independent association of Homer I with TRPC1 and IP3RII. In addition, thapsigargin and thrombin enhanced the association of Homer1 with STIM1 and Orai1 in a Ca2+-dependent manner. Interference with Homer function by introduction of the synthetic PPKKFR peptide into cells, which emulates the proline-rich sequences of the PPXXF motif, reduced STIM1 Orai1 and TRPC1-IP3RII associations, as compared with the introduction of the inactive PPKKRR peptide. The PPKKFR peptide attenuates thrombin-evoked Ca2+ entry and the maintenance of thapsigargin-induced store-operated Ca2+ entry. Finally, the PPKKFR peptide attenuated thrombin-induced platelet aggregation. The findings of the present study support an important role for Homer proteins in thrombin-stimulated platelet function, which is likely to be mediated by the support of agonist-induced Ca2+ entry.
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