Chemokine receptors intracellular signaling

Figure 16.1 Mechanisms of chemokine inhibition by the CKBPs encoded by pathogens. Chemokines interact with CACs present at the surface ofendothelial cells and are presented to the leukocytes. The chemokine receptors expressed at the surface of leukocytes interact with chemokines and intracellular signaling is triggered to induce cell migration. The CKBPs may have broad chemokine binding specificity, such as the poxvirus 35-kDa protein, the gammaherpesvirus M3 protein orthe MYXVM-...

Finally, during budding, HIV-1 may also incorporate into its membrane envelope a variety of different molecules, including proteins that may subsequently interact with their counterparts on the host cell membrane (reviewed in ref. 192), resulting in intracellular signaling and facilitation of virus fusion (193,194). However, the incorporation of cell membrane-derived molecules does not appear to be an absolute requirement for virus entry (195), indicating the leading role of CD4 and the coreceptor for any such mechanism. However, this phenomenon may account for lower levels of inhibition when the effects of mutant CD4 and/or chemokine receptor are studied. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

The intracellular signals involved in chemo-taxis are not yet fully understood, and much of the information available today has been deduced from signaling information for other GPCRs. However, significant new data regarding the chemotactic process have accumulated in recent years. Like other seven-transmembrane receptors, chemokine receptors couple to G-proteins. Many chemokine-in-duced signaling events are inhibited by Borde-tella pertussis toxin (PTX), suggesting that chemokine receptors are linked to G-proteins of the Gai class (18,19). In cotransfection experiments it has been shown that CXCRl and... 

Activation of the chemokine receptor leads to rapid activation of phosphoinositide-spe-cific phospholipases, which leads to inositol-1,4,5-triphosphate formation and a transient rise in intracellular calcium (18). Phospholipase C (PLC) isoforms that are involved in chemokine receptor activation become activated by direct interaction with the J3y subunits. In addition to its interaction with PLCs, the j3y subunits also interact with the type phosphoinositol 3 kinase y (PISKy), and activation of this enzyme results in the formation of PtdIns(3,4,5)P3 (17). Mice that do not express PI3Ky have severely impaired chemo-kine-stimulated signal transduction, and PKB is not activated, suggesting an important role for this pathway in the chemotactic process (27-29). Although leukocytes isolated from these mice showed a decrease in cell chemo-taxis, the response is not completely lost, and under conditions of complete PI3Ky inhibition, neutrophils can still chemotax in response to chemokines (30). 

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