Defective chemoattractant-induced calcium signalling in S100A9 null neutrophils

Cell Calcium. 2007 Feb;41(2):107-21. doi: 10.1016/j.ceca.2006.05.004. Epub 2006 Jun 30.

Abstract

The S100 family member S100A9 and its heterodimeric partner, S100A8, are cytosolic Ca2+ binding proteins abundantly expressed in neutrophils. To understand the role of this EF-hand-containing complex in Ca2+ signalling, neutrophils from S100A9 null mice were investigated. There was no role for the complex in buffering acute cytosolic Ca2+ elevations. However, Ca2+ responses to inflammatory agents such as chemokines MIP-2 and KC and other agonists are altered. For S100A9 null neutrophils, signalling at the level of G proteins is normal, as is release of Ca2+ from the IP(3) receptor-gated intracellular stores. However MIP-2 and FMLP signalling in S100A9 null neutrophils was less susceptible than wildtype to PLCbeta inhibition, revealing dis-regulation of the signalling pathway at this level. Downstream of PLCbeta, there was reduced intracellular Ca2+ release induced by sub-maximal levels of chemokines. Conversely the response to FMLP was uncompromised, demonstrating different regulation compared to MIP-2 stimulation. Study of the activity of PLC product DAG revealed that chemokine-induced signalling was susceptible to inhibition by elevated DAG with S100A9 null cells showing enhanced inhibition by DAG. This study defines a lesion in S100A9 null neutrophils associated with inflammatory agonist-induced IP3-mediated Ca2+ release that is manifested at the level of PLCbeta.

MeSH terms

  • Animals
  • Calcium Signaling*
  • Calgranulin B / genetics
  • Calgranulin B / metabolism*
  • Cells, Cultured
  • Chemokine CXCL2
  • Chemokines / pharmacology
  • Chemotactic Factors / pharmacology*
  • Diglycerides / metabolism
  • Estrenes / pharmacology
  • Homeostasis
  • Inositol 1,4,5-Trisphosphate Receptors / physiology
  • Mice
  • Mice, Knockout
  • Models, Biological
  • N-Formylmethionine Leucyl-Phenylalanine / analogs & derivatives
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Neutrophils / drug effects
  • Neutrophils / metabolism*
  • Pyrrolidinones / pharmacology
  • Type C Phospholipases / antagonists & inhibitors

Substances

  • Calgranulin B
  • Chemokine CXCL2
  • Chemokines
  • Chemotactic Factors
  • Cxcl2 protein, mouse
  • Diglycerides
  • Estrenes
  • Inositol 1,4,5-Trisphosphate Receptors
  • Pyrrolidinones
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • N-Formylmethionine Leucyl-Phenylalanine
  • N-formylmethionyl-leucyl-phenylalanyl-lysine
  • Type C Phospholipases