NA+ CHANNELS AND EXCITABILITY IN HYPOXIA

  • Spray, David C. (PI)
  • Iacobas, Dumitru Andrei (PI)
  • Siegel, Norman (PI)
  • Boron, Walter F. (PI)
  • Siegel, Norman (PI)
  • Lister, George (PI)
  • Gaudio, Karen (PI)
  • Behar, Kevin (PI)
  • Boron, Walter F. (PI)
  • Kashgarian, Michael (PI)
  • Haddad, Garbiel (PI)
  • Boron, Walter F. (PI)
  • Gaudio, Karen (PI)
  • Behar, Kevin (PI)
  • Boron, Walter F. (PI)
  • Kashgarian, Michael (PI)
  • Haddad, Garbiel (PI)

Project: Research project

Project Details

Description

In the past several years, one main focus of our laboratory has been to
examine the response of central neurons in a number of brain regions to
acute and chronic O2 deprivation. We are particularly interested in the
mechanisms that can led to neuronal injury and those that, when
activated, can prevent or delay injury. Recently, we have made
interesting observations regarding membrane ionic events that link
metabolism to excitability. One of these observations pertains to the
voltage-sensitive Na+ channels in central neurons. An early event during
anoxia in mature (adult) neocortical neurons seems to be a profound
inhibition of the steady-state availability of these channels with a
major reduction in Na+ current (iNa) and a decrease in neuronal
excitability. This observation is important because this may be an
adaptive strategy in the adult in that the decrease in excitability will
lessen O2 consumption and minimize the mismatch between demand and
supply. We are not sure how the immature neocortical cells will respond
in terms of INa. We therefore focus in this proposal on the study of the
Na+ current in neocortical neurons during graded hypoxia and examine 4
separate hypotheses: 1+ Neocortical neurons decrease their excitability
during graded hypoxia by inhibiting INa in a graded manner in the mature
but not in the immature; 2) the alterations in INa kinetics during O2
deprivation in neocortical neurons are due to changes in specific
cytosolic factors and these are more pronounced in the mature than in the
immature; 3) O2 deprivation alters INa via mechanisms that are either
membrane-delimited or dependent on phosphorylation and 4) long term
hypoxia modulates the expression of Na+ channels. These experiments will
involve the use of the in-vitro slice and microelectrode technique as
well as patch clamp with whole-cell and single channel recordings in
freshly dissociated neurons. Optical measurements of Ca++ i and H+ i
using confocal microscopy will also be performed. All techniques are
available and routinely performed in the PI's laboratory. Our long term
view and efforts are focussed on understanding the events that occur
during anoxia in central neurons so that we can manipulate cell behavior
and possibly render mammalian neurons more tolerant to lack of O2. This
will have major implications on a vast number of diseases or conditions
that span the age spectrum from the fetus to old age.
StatusFinished
Effective start/end date1/1/017/31/11

ASJC

  • Nephrology
  • Cardiology and Cardiovascular Medicine
  • Genetics
  • Molecular Biology
  • Physiology
  • Biochemistry
  • Cell Biology
  • Physiology (medical)
  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Spectroscopy
  • Pathology and Forensic Medicine
  • Statistics, Probability and Uncertainty
  • Immunology

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