ABSTRACT
Integrin-mediated migration of leukocytes is directed by a heterogeneous group of components known as chemoattractants. Many chemoattractants transmit signals through heterodimeric G-protein coupled receptors (Fig. 5). GPCRs transmit their signals through the α-subunit of Gia, which may be inhibited by pertussis toxin. A key pathway mediated by GPCRs is signaling through class Ib phosphatylinositol3-kinase (PI3-kinase), containing the p110γ catalytic subunit. PI3k-γ is recruited to the inner leafl et of the cell membrane by the G-protein βγ sbunit, where it becomes activated. Th e second pathway linked to PI3-kinase activation is induced by the fMLP receptor on neutrophils and leads to the activation of p38 MAPK and downstream activation of Rac. Rac induces actin polymerization through actinbinding proteins WAVE (Scar) and Arp2/3. Th e third, PI3-kinase-dependent pathway is common with that induced through TCR and FcRs and involves tyrosine kinases Lck and Zap-70 followed by signaling to class Ia PI3-kinases and its p110∂ subunit, and activation of Akt as well as GTPases Rac and Cdc42. In addition to PI3-kinase activation, GPCRs mediate their signals through small GTPase (Ley et al. 2007). In monocytes, ligation of GPCRs results in rapid activation of PLC leading to intracellular infl ux of Ca2+. Ca2+ and diacylglycerol activate the proteins of small GTPase family-Rac, activated by guanine nucleotide exchange factors, Ras-related protein 1 (Rap1) and Ras homologue gene-family member A (RhoA)—required for αLβ2 affi nity.
