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NEUROLOGY 1996;47:741-750
© 1996 American Academy of Neurology

Decreased receptor-mediated calcium response in prion-infected cells correlates with decreased membrane fluidity and IP sub 3 release

K. Wong, MD, Y. Qiu, MD, PhD, W. Hyun, MS, R. Nixon, MD, PhD, J. VanCleff, J. Sanchez-Salazar, S. B. Prusiner, MD and S. J. DeArmond, MD, PhD

From the Departments of Pathology (Drs. Wong, Qiu, Nixon, and VanCleff, Ms. Sanchez-Salazar, and Dr. DeArmond), Neurology (Drs. DeArmond and Prusiner), Laboratory Medicine (Mr. Hyun), Biochemistry and Biophysics (Dr. Prusiner), University of California, San Francisco, CA.
Supported by grants from the National Institutes of Health (NS14069, AG08967, AG02132, and NS22786) and the American Health Assistance Foundation, as well as gifts from the Sherman Fairchild and Bernard Osher Foundations.
Received January 26, 1996. Accepted in final form March 27, 1996.
Address correspondence and reprint requests to Dr. Stephen J. DeArmond, Department of Pathology, University of California, San Francisco, CA 94143-0506.

The most characteristic neuropathologic features of prion diseases are accumulation of PrP sup Sc in the brain and vacuolation of neurons.Neuronal vacuolation suggests plasma membrane dysfunction. In an earlier study, we found that bradykinin (Bk)-stimulated Ca2+ responses in scrapie-infected ScN2 a cells were reduced by 30 to 50% compared with uninfected N2 a cells. In this study, we investigated the cause. The IP3 second-messenger response to Bk stimulation was reduced by 90%, indicating that a defect occurs in the plasma membrane. Receptor-binding assays showed a 3- to 4-fold increase in Bk receptor numbers on ScN2 a cells; however, their binding affinity was reduced 5- to 13-fold, which may account for the decreased IP3 and Ca2+ responses. These results argue that scrapie causes a more fundamental change in the properties of the plasma membrane. We verified this by fluorescence recovery after photobleaching (FRAP) analysis with a lipid probe that measures lateral membrane fluidity. A 7-fold reduction of fluidity was found. These results support the hypothesis that the conversion of PrPC to PrPSc or the accumulation of PrPSc in scrapie-infected cells alters the composition of their plasma membranes that secondarily causes the abnormal receptor-mediated function.

NEUROLOGY 1996;47: 741-750




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