Project Details

Description

The purpose of this project is to continue work carried out by our group
over the past 13 years on the metabolic properties of the myelin sheath.
Present emphasis is on the role of receptors which produce second
messengers within the myelin complex, and the enzymatic reactions
involved in the formation and inactivation of such messengers. Following
our observations on receptor-mediated activation of phosphoinositide
phosphodiesterase and adenylyl cyclase, we plan to follow up preliminary
observations myelin also contains guanylyl cyclase activity leading to
the synthesis of two products: 3',5'-cGMP and 2',3'-cGMP. The latter is
of special interest because it is potentially the in situ substrate for
myelin-associated 2',3'-cyclic nucleotide phosphodiesterase (CNP); the
function of the latter enzyme has been one of the long-standing mysteries
in the myelin field. We plan to prove unequivocally that this is the
product formed, and to characterize as fully as possible the kinetic and
related properties of the two guanylyl cyclases. In the case of the
cyclase catalyzing formation of the 3',5' isomer, which we hypothesize to
be a second messenger, we shall attempt to find an agonist that activates
the enzyme; this will involve incubation of myelin with [3H]GTP and
various agonists (e.g.. natriuretic peptides, prostaglandin, angiotensin)
that have been shown to activate a similar enzyme in other systems. It
is also possible that the 2',3' isomer is formed as a second messenger,
but that will not be pursued during the coming period. An additional
signal transduction mechanism which we have discovered to occur in myelin
is phosopholipase D-catalyzed cleavage of phosphatidylcholine, leading to
phosphatidic acid. We shall investigate the enzymology of that reaction,
explore possible agonists that trigger it, and determine whether the
final product is phosphatidic acid or diacylglycerol; the latter is a
possibility to be considered since it is known that myelin contains
phosphatidate phosphohydrolase. Finally, we shall investigate two
enzymes involved in the phosphoinositide cycle to determine whether this
cycle occurs in a manner requiring concerted action of both axon and
myelin.
StatusFinished
Effective start/end date4/1/805/31/99

Funding

  • National Institutes of Health
  • National Institutes of Health: $130,145.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $182,627.00
  • National Institutes of Health: $195,034.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $138,691.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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