Normal hematopoiesis and inflammatory responses despite discrete signaling defects in Gα15 knockout mice

被引:36
作者
Davignon, I
Catalina, MD
Smith, D
Montgomery, J
Swantek, J
Croy, J
Siegelman, M
Wilkie, TM
机构
[1] Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75235 USA
[2] Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75235 USA
[3] Univ Texas, Ctr Parasitol, Dept Biol, Arlington, TX 76019 USA
[4] Univ Texas, SW Med Ctr, Dept Physiol, Dallas, TX 75235 USA
关键词
D O I
10.1128/MCB.20.3.797-804.2000
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
G alpha 15 activates phospholipase C beta in response to the greatest variety of agonist-stimulated heptahelical receptors among the four Gq class G-protein alpha subunits expressed in mammals. G alpha 15 is primarily expressed in hematopoietic cells in fetal and adult mice. We disrupted the G alpha 15 gene by homologous recombination in embryonic stem cells to identify its biological functions. Surprisingly, hematopoiesis was normal in G alpha 15(-/-) mice, G alpha 15(-/-) G alpha q(-/-) double-knockout mice (which express only G alpha 11 in most hematopoietic cells), and G alpha 11(-/-) mice, suggesting functional redundancy in Gq class signaling. Inflammatory challenges, including thioglycolate-induced peritonitis and infection with Trichinella spiralis, stimulated similar responses in G alpha 15(-/-) adults and wild-type siblings. Agonist-stimulated Ca2+ release from intracellular stores was assayed to identify signaling defects in primary cultures of thioglycolate-elicited macrophages isolated from G alpha 15(-/-) mice. C5a-stimulated phosphoinositide accumulation and Ca2+ release was significantly reduced in Ga15(-/-) macrophages. Ca2+ signaling was abolished only in mutant cells pretreated with pertussis toxin, suggesting that the C5a receptor couples to both G alpha 15 and G alpha i in vivo. Signaling evoked by other receptors coupled by Gq class alpha subunits appeared normal in Ga15-/- macrophages. Despite discrete signaling defects, compensation by coexpressed Gq and/or Gi class alpha subunits may suppress abnormalities in G alpha 15-deficient mice.
引用
收藏
页码:797 / 804
页数:8
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