Death receptors, ligands

Delmas D, Rebe C, Micheau O, Athias A, Gambert P, Grazide S, Laurent G, Latruffe N, Solary E. 2004. Redistribution of CD95, DR4 and DR5 in rafts accounts for the synergistic toxicity of resveratrol and death receptor ligands in colon carcinoma cells. Oncogene 23 8979-8986. 

Like other receptors, death receptors are activated by binding ligands. The activated death receptor-ligand complex is linked with its death domain (DD) to a homologous DED (death effector region), repeated in tandem, and recruits a zymogen form of a protease, pro-caspase 8 (Fig. 13.1). But the linker is, like other linkers, versatile. 

Table 13.1 Death Receptors and Death Receptor Ligands Associated with the Extrinsic Pathway of Apoptosis...

Binding of death receptor ligand to death receptor induces apoptosis. 

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

Reynaud M, Petit G, Potard D, et al Six deaths linked to concomitant use of buprenor-phine and benzodiazepines. Addiction 93 1383-1392, 1998 Richards JG, Martin JR Binding profiles and physical dependence liabilities of selected benzodiazepine receptor ligands. Brain Res Bull 43 381-387, 1998... 

Death receptor activation. Several different ligands can induce apoptosis of neural cells including certain cytokines... 

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

The death ligand and the death receptor There is, on the surface of the cytotoxic T cell, a ligand that binds to a specific receptor on the infected cell known as a death receptor. The ligand is known as the FAS ligand (or death ligand). This binding results, via activation of intracellular proteases, in stimulation of the caspase system, which initiates apoptosis (Figure 17.31). (See Chapter 20 for description of apoptosis.)... 

Figure 17.31 Death of virally infected host celis via the death receptor on the host cell to which is bound the death ligand on the surface of the cytotoxic T-cell. The interaction between the ligand and the receptor results in activation of caspases that induce apoptosis. The latter process results in disintegration of the cell, the results of which are apoptotic vesicles that are phagocytosed and destroyed by the macrophages.

Jung EM, Lim JH, Lee TJ, Park JW, Choi KS, Kwon TK. 2005. Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). 

The extrinsic pathway consists of a series of events initially induced by death receptors located on the cell surface. It is initiated by interaction of extracellular death ligands with their respective receptors, located on the surface of the plasma membrane. The death ligands are members of the tumor necrosis factor (TNF)/nerve growth factor (NGF) superfamily. TNF-R1, Fas (Apo-l/CD95), TRAIL-R1, TRAIL-R2, and NGF-R are examples of death receptors. They are transmembrane proteins consisting of an external domain, where the ligand associates, and a cytoplasmic domain, which contains the DD (death domain). 

---