The objectives of this proposal are: 1) to study sodium channel inactivation in rat skeletal muscle, and 2) to investigate rat model of human muscle myotonic disorders in which membrane excitability may be impaired. Two hypotheses about sodium channel gating will be tested. First, that sodium currents are increased by treatments which produce myotonia in rat skeletal muscle. Second, that the increase in sodium current density is due to an alteration in voltage-dependent sodium channel inactivation. The techniques employed are: 1) the loose-patch voltage clamp will be used to measure sodium currents, and 2) the fiber type of single fibers will be determined by histochemical staining and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The experiments measure sodium currents in control and myotonic muscle using techniques developed in this laboratory that permit stable current recordings of cells for several hours. Myotonia in rat muscle will be produced by: 1) bathing a fiber in a chloride- deficient solution, 2) treating fibers with aromatic carboxylic acids to reduce chloride conductance, and 3) treating rats with 20, 25-diazacholesterol. The voltage dependence of sodium channel fast and slow inactivation will be studied to examine whether changes in sodium current density can be attributed to alterations in fast or slow inactivation. These projects will provide 1) new information on the excitability of mammalian skeletal muscle; and 2) possibly new information on the pathophysiology of different forms of myotonia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026661-03
Application #
3412643
Study Section
Physiology Study Section (PHY)
Project Start
1989-08-01
Project End
1992-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Ruff, Robert L; Lennon, Vanda A (2008) How myasthenia gravis alters the safety factor for neuromuscular transmission. J Neuroimmunol 201-202:13-20
Kaminski, H J; Ruff, R L (1993) Insights into possible skeletal muscle nicotinic acetylcholine receptor (AChR) changes in some congenital myasthenias from physiological studies, point mutations, and subunit substitutions of the AChR. Ann N Y Acad Sci 681:435-50
Ruff, R L; Whittlesey, D (1993) Na+ channel distribution and inactivation properties of human type 1 and 2 muscle fibers. Ann N Y Acad Sci 681:412-4
Kaminski, H J; Ruff, R L (1992) Congenital disorders of neuromuscular transmission. Hosp Pract (Off Ed) 27:73-81, 85
Ruff, R L; Whittlesey, D (1992) Na+ current densities and voltage dependence in human intercostal muscle fibres. J Physiol 458:85-97
Ruff, R L (1992) Na current density at and away from end plates on rat fast- and slow-twitch skeletal muscle fibers. Am J Physiol 262:C229-34
Ruff, R L; Whittlesey, D (1991) Ca-, Sr-tension relationships and contraction velocities of human muscle fibers. Muscle Nerve 14:1219-26
Ruff, R L (1991) Calcium-tension relationships of muscle fibers from patients with periodic paralysis. Muscle Nerve 14:838-44
Ruff, R L; Weissman, J (1991) Iodoacetate-induced contracture in rat skeletal muscle: possible role of ADP. Am J Physiol 261:C828-36
Ruff, R L; Spiegel, P (1990) Ca sensitivity and acetylcholine receptor currents of twitch and tonic snake muscle fibers. Am J Physiol 259:C911-9

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