Normal hematopoiesis and inflammatory responses despite discrete signalingdefects in G alpha 15 knockout mice

G alpha 15 activates phospholipase C beta in response to the greatest varie ty of agonist-stimulated heptahelical receptors among the four Gq class G-p rotein alpha subunits expressed in mammals. G alpha 15 is primarily express ed in hematopoietic cells in fetal and adult mice. We disrupted the G alpha 15 gene by homologous recombination in embryonic stem cells to identify it s biological functions. Surprisingly, hematopoiesis was normal in G alpha 1 5(-/-) mice, G alpha 15(-/-) G alpha q(-/-) double-knockout mice (which exp ress only G alpha 11 in most hematopoietic cells), and G alpha 11(-/-) mice , suggesting functional redundancy in Gq class signaling. Inflammatory chal lenges, including thioglycolate-induced peritonitis and infection with Tric hinella spiralis, stimulated similar responses in G alpha 15(-/-) adults an d wild-type siblings. Agonist-stimulated Ca2+ release from intracellular st ores was assayed to identify signaling defects in primary cultures of thiog lycolate-elicited macrophages isolated from G alpha 15(-/-) mice. C5a-stimu lated phosphoinositide accumulation and Ca2+ release was significantly redu ced in Ga15(-/-) macrophages. Ca2+ signaling was abolished only in mutant c ells pretreated with pertussis toxin, suggesting that the C5a receptor coup les to both G alpha 15 and G alpha i in vivo. Signaling evoked by other rec eptors coupled by Gq class alpha subunits appeared normal in Ga15-/- macrop hages. Despite discrete signaling defects, compensation by coexpressed Gq a nd/or Gi class alpha subunits may suppress abnormalities in G alpha 15-defi cient mice.