Function and regulation of chemoattractant receptors

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Phagocyte migration and activation rely on chemoattractant receptors coupled to G-proteins.
• Previous work established G-protein-mediated phospholipase C activation by chemoattractants.

Purpose of the Study:

• To elucidate mechanisms of chemoattractant receptor function, regulation, and cross-regulation.
• To investigate distinct signaling pathways for chemotaxis and exocytosis.

Main Methods:

• Development of cellular and animal models for biochemical, cell biological, and molecular genetic analyses.
• Examination of receptor phosphorylation by G-protein-coupled receptor kinases and protein kinase C.
• Analysis of G-protein activation modulation by regulators of G-protein signaling (RGS) and phospholipase C modification.
• Generation and study of gene-targeted mice deficient in leukotriene B4 receptors.

Main Results:

• Chemoattractant receptors activate separate pathways for chemotaxis and exocytosis.
• Receptor function is cross-regulated at multiple levels, notably through phosphorylation.
• Phospholipase C activation is regulated distally to receptor phosphorylation, involving RGS proteins and phospholipase C modification.
• Phospholipase Cbeta3 phosphorylation by protein kinase A and C was demonstrated.
• Mice lacking leukotriene B4 receptors showed reduced neutrophil accumulation and sex-specific anaphylaxis differences.

Conclusions:

• Chemoattractant receptor signaling is complex, involving distinct pathways and intricate regulatory mechanisms.
• Phosphorylation and RGS proteins play critical roles in modulating receptor activity and downstream responses.
• Mouse models are valuable for understanding the in vivo function and regulation of chemoattractant receptors in inflammation.