The proposed work is ultimately directed to elucidating the biophysical basis of nervous dysfunction in demyelinating disease. Changes will be sought in the pattern of distribution of sodium channels, of potassium channels, and of sodium pumps in the nerve membrane during the processes of normal myelination (in the newborn animal) and of demyelination, produced experimentally in a number of ways. A variety of electrophysiological and pharmacological techniques will be used. Voltage-clamp experiments will be done to determine the Hodgkin-Huxley parameters for mammalian myelinated nerve at different temperatures. Based on the temperature dependences of the various parameters, computer simulation of the mammalian action potential at 37 C will be done. Sodium and potassium currents in voltage-clamp experiments will be used to examine sodium and potassium channels. The sensitivity of the compound action potential to 4-aminopyridine will be used to study potassium channels in situations (e.g. demyelination) where voltage clamping is not feasible. The electrophysiological consequence of myelination will be examined experimentally. Labelled saxitoxin will be used as a marker for sodium channels; a search will be made for a corresponding high affinity marker for potassium channels. Labelled ouabain will be used as a marker for sodium pumps.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS012327-11
Application #
3394787
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1975-06-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
11
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
Pappas, C A; Ritchie, J M (1998) Effect of specific ion channel blockers on cultured Schwann cell proliferation. Glia 22:113-20
Ripellino, J A; Neve, R L; Howe, J R (1998) Expression and heteromeric interactions of non-N-methyl-D-aspartate glutamate receptor subunits in the developing and adult cerebellum. Neuroscience 82:485-97
Baker, M D; Ritchie, J M (1996) Characteristics of type I and type II K+ channels in rabbit cultured Schwann cells. J Physiol 490 ( Pt 1):79-95
Belcher, S M; Zerillo, C A; Levenson, R et al. (1995) Cloning of a sodium channel alpha subunit from rabbit Schwann cells. Proc Natl Acad Sci U S A 92:11034-8
Baker, M D; Ritchie, J M (1994) The action of capsaicin on type I delayed rectifier K+ currents in rabbit Schwann cells. Proc Biol Sci 255:259-65
Baker, M; Howe, J R; Ritchie, J M (1993) Two types of 4-aminopyridine-sensitive potassium current in rabbit Schwann cells. J Physiol 464:321-42
Utzschneider, D A; Thio, C; Sontheimer, H et al. (1993) Action potential conduction and sodium channel content in the optic nerve of the myelin-deficient rat. Proc Biol Sci 254:245-50
Howe, J R; Baker, M; Ritchie, J M (1992) On the block of outward potassium current in rabbit Schwann cells by internal sodium ions. Proc Biol Sci 249:309-16
Howe, J R; Ritchie, J M (1992) Multiple kinetic components of sodium channel inactivation in rabbit Schwann cells. J Physiol 455:529-66
Ritchie, J M (1991) Current perspectives in glial electrophysiology. Ann N Y Acad Sci 633:331-42

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