The principal objective of this proposal is to test whether phospholipids, primarily the inositides, play a role in impulse propagation. As a first step, three nerve preparations, chosen for their widely differing levels of excitable membrane, will be used in experiments to determine if axolemmal membrane lipid metabolism is affected by electrical stimulation or membrane depolarization. Studies with different labeled precursors will delineate those steps of lipid metabolism that respond to electrical stimulation and/or membrane depolarization while followup quantitative EM autoradiographic studies will localize lipid changes (synthesis or breakdown) to excitable axon membranes. If lipid metabolism is responsive to nerve excitation, enzyme studies will address questions of how lipid metabolism of excitable membranes is regulated, with emphasis on the roles of calcium and enzyme lipid interaction, and how lipid changes could influence ion channel and/or pump activities. A separate approach to establish a relationship between excitability and lipids will be with animal models, Wallerian degeneration and diabetic neuropathy, displaying defective nerve conduction. These studies will serve to find out whether altertations in membrane lipids could underlie loss of excitability in these experimental models. The secondary objective of this proposal is to initiate studies that will lead to the establishment of a role for lipid metabolism in presynaptic nerve terminal function. As a first step, studies will address the localization of lipid metabolism to presynaptic terminals. Biochemical studies will be directed toward showing that lipid enzymes are components of secretory and endocytic vesicles. Autoradiographic studies, initially with tritiated inositol and choline, will determine whether the synthesis of lipids occurs in presynaptic terminals. These studies will be followed by others to find out whether lipid changes accompany neurotransmitter release and vesicle recycling. The possibility that calcium regulated lipolysis plays a role in terminal function will be examined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS013980-10
Application #
3395375
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-09-30
Project End
1988-11-30
Budget Start
1986-09-01
Budget End
1987-11-30
Support Year
10
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Institute for Basic Research in Dev Disabil
Department
Type
DUNS #
167205090
City
Staten Island
State
NY
Country
United States
Zip Code
10314
Gould, R M; Byrd, A L; Barbarese, E (1995) The number of Schmidt-Lanterman incisures is more than doubled in shiverer PNS myelin sheaths. J Neurocytol 24:85-98
Spivack, W D; Zhong, N; Salerno, S et al. (1993) Molecular cloning of the myelin basic proteins in the shark, Squalus acanthias, and the ray, Raja erinacia. J Neurosci Res 35:577-84
Kitagawa, K; Sinoway, M P; Yang, C et al. (1993) A proteolipid protein gene family: expression in sharks and rays and possible evolution from an ancestral gene encoding a pore-forming polypeptide. Neuron 11:433-48
Alberghina, M; Gould, R M (1992) Characterization of phospholipase A2 and acyltransferase activities in squid (Loligo pealei) axoplasm: comparison with enzyme activities in other neural tissues, axolemma and axoplasmic subfractions. Neurochem Int 21:563-71
Gould, R M; Mattingly, G (1990) Regional localization of RNA and protein metabolism in Schwann cells in vivo. J Neurocytol 19:285-301
Gould, R M; Armstrong, R (1989) Use of lead aspartate block staining in quantitative EM autoradiography of phospholipids: application to myelinating peripheral nerve. J Histochem Cytochem 37:1393-9
Toews, A D; Armstrong, R; Ray, R et al. (1988) Deposition and transfer of axonally transported phospholipids in rat sciatic nerve. J Neurosci 8:593-601
Tanaka, T; Yamaguchi, H; Kishimoto, Y et al. (1987) Lipid metabolism in various regions of squid giant nerve fiber. Biochim Biophys Acta 922:85-94
Gould, R M; Connell, F; Spivack, W (1987) Phospholipid metabolism in mouse sciatic nerve in vivo. J Neurochem 48:853-9
Gould, R M; Holshek, J; Silverman, W et al. (1987) Localization of phospholipid synthesis to Schwann cells and axons. J Neurochem 48:1121-31

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