All quiet on the neuronal front: NMDA receptor inhibition by prion protein

Abstract

The normal function of the prion protein (PrP)-the causative agent of mad cow or prion disease-has long remained out of reach. Deciphering PrP's function may help to unravel the complex chain of events triggered by PrP misfolding during prion disease. In this issue of the JCB, an exciting paper (Khosravani, H., Y. Zhang, S. Tsutsui, S. Hameed, C. Altier, J. Hamid, L. Chen, M. Villemaire, Z. Ali, F.R. Jirik, and G.W. Zamponi. 2008. J. Cell Biol. 181:551-565) connects diverse observations regarding PrP into a coherent framework whereby PrP dampens the activity of an N-methyl-d-aspartate (NMDA) receptor (NMDAR) subtype and reduces excitotoxic lesions. The findings of this study suggest that understanding the normal function of proteins associated with neurodegenerative disease may elucidate the molecular pathogenesis.

Figure 1.

PrP may directly interact with the NR2D subunit of NMDAR to regulate its activity. (A) In wild-type neurons, PrP silences the NR2D-containing NDMAR, preventing depolarization and calcium entry. (B) In PrP-null neurons, the NR2D-containing NMDAR opens much more readily, leading to excessive calcium entry and more severe excitotoxic injury during conditions of excessive glutamate release. Magnesium, which blocks NMDAR at resting potential, is not depicted.