Sci. STKE, 16 November 2004
GPCRs Getting Back Together Sends a Message
Members of the long N-terminus, group B (LNB) heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPCR) subfamily are constitutively cleaved into an N-terminal fragment (NTF, which contains cell adhesion domains) and a C-terminal fragment (CTF, which contains the seven-transmembrane GPCR domain). Latrophilin, a presynaptic LNB involved in regulating neurotransmitter release, is stimulated by α-latrotoxin (a component of black widow spider venom) binding to the NTF to activate phospholipase C (PLC) signaling, thereby increasing release of calcium from intracellular stores. Volynski et al. expressed latrophilin in COS7 cells and showed that latrophilin proteolysis took place in the endoplasmic reticulum and that only cleaved fragments appeared on the cell surface. The authors used a series of latrophilin CTF mutants to show that the seven amino acids of CTF immediately downstream of the cleavage site were necessary for latrophilin proteolysis and that their presence in the CTF promoted NTF anchoring in the cell membrane. However, NTF could anchor independently of CTF, and the two proteins behaved independently of each other at the cell surface. A latrotoxin derivative, LTXN4C, activated PLC and stimulated an increase in intracellular calcium in neuroblastoma cells transfected with latrophilin (but not cells expressing a latrophilin mutant lacking the CTF transmembrane regions) and promoted the formation of NTF-CTF complexes. Thus, the authors propose that, whereas the two fragments can act independently, agonist binding to the NTF promotes NTF association with CTF, leading to the activation of CTF-mediated cell signaling pathways.
K. E. Volynski, J.-P. Silva, V. G. Lelianova, M. A. Rahman, C. Hopkins, Y. A. Ushkaryov, Latrophilin fragments behave as independent proteins that associate and signal on binding of LTXN4C. EMBO J. 23, 4423-4433 (2004). [Online Journal]
Citation: Getting Back Together Sends a Message. Sci. STKE 2004, tw412 (2004).
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